IT8147902A1

IT8147902A1 - TOPICAL PHARMACEUTICAL PREPARATIONS CONTAINING ALKANE-CARBOXYL ACID SALTS, AS WELL AS NEW CARBOXYLIC ACID SALTS AND PROCEDURE FOR PRODUCING THEM.

Info

Publication number: IT8147902A1
Application number: IT1981A47902A
Authority: IT
Original assignee: Eckert Theodor
Priority date: 1981-02-27
Filing date: 1981-02-27
Publication date: 1982-08-27
Also published as: IT8147902A0; IT1195318B

Description

Descrizione dellinvenzione industriale dal titolo; "PREPARATI FARMACEUTICI TOPICI, CONTENENTI SALI DI ACIDI ALCAN-CARBOSSILICI, NOHCHE' NOVI SALI DI ACIDI CARBOSSILICI E PROCEDIMENTO PER PRODURLI? Description of the industrial invention entitled; "TOPICAL PHARMACEUTICAL PREPARATIONS CONTAINING ALCAN-CARBOXYL ACID SALTS, NOH WHICH NOVI CARBOXYL ACID SALTS AND PROCEDURE FOR PRODUCING THEM?

RIASSUNTO SUMMARY

L'invenzione riguarda preparati farmaceutici applicabili in modo topico, contenenti sali di aci di alcan-carbossilici, in particolare composti della formula The invention relates to topically applicable pharmaceutical preparations, containing salts of alkane-carboxylic acids, in particular compounds of the formula

(I) (THE)

in cui R1 rappresenta un gruppo della formula where R1 represents a group of the formula

(IIa) (IIa)

nella quale X1 ed X2 iudicano idrogeno ed X3 indica isobuti?e, oppure ed X^ rappresentano idrogeno ed X2 rappresenta benzoile, oppure X1 indica idrogeno, X2 ?ndica cloro ed X3 indica 5-pirrolin-l-ile, oppure X1 rappresenta idrogeno, ? rappresenta un gruppo della formula in which X1 and X2 indicate hydrogen and X3 indicates isobutes? and, or and X ^ represent hydrogen and X2 represents benzoyl, or X1 indicates hydrogen, X2? ndic chlorine and X3 indicates 5-pyrrolin-1-yl, or X1 represents hydrogen, ? represents a group of the formula

insieme con X4 rappresenta un legame, ed R2 indica together with X4 represents a bond, and R2 indicates

ogni volta metile, oppure X2 ed X3 rappresentano each time methyl, or X2 and X3 represent

idrogeno ed X1 rappresenta 2,6-dicloro-anilino, ed hydrogen and X1 represents 2,6-dichloro-aniline, ed

R2 indica idrogeno, oppure R1 indica un gruppo del R2 indicates hydrogen, or R1 indicates a group of

la formula the formula

(Ib) (Ib)

nella quale X5 rappresenta il.legame in comune eoa in which X5 represents the common link eoa

il gruppo metinico della formula I, X6 ed X7 indica the methine group of the formula I, X6 and X7 indicates

no idrogeno, X8 rappresenta p-metilbenzo?le, Y ? un no hydrogen, X8 represents p-methylbenzo? le, Y? a

atomo di azoto ed X9 indica un gruppo metilico, op-pure X5 ? un gruppo metilico, X6 rappresenta un legame in comune con il gruppo metinico nella formula atom of nitrogen and X9 indicates a methyl group, or X5? a methyl group, X6 represents a common bond with the methyl group in the formula

I, Xp indica un gruppo della formula I, Xp denotes a group of the formula

X8 insieme con X10 rappresenta un legame, I ? un ato. X8 together with X10 represents a bond, I? an ato.

mo d? azoto, ed indica p-clorobenzoile, oppure X5mo d? nitrogen, and indicates p-chlorobenzoyl, or X5

? un gruppo metilico, X6 rappresenta il legame in coma ne con il gruppo metinico nella formula X, X7 indica ? a methyl group, X6 represents the bond in coma with the methyl group in the formula X, X7 indicates

un gruppo della formula , X8 insie a group of the formula, X8 sets

me con X11 indica un legame, I ? un atomo di G, ed rappresenta (p-iaetansolfinilfenil)-met?lene, ed me with X11 indicates a link, I? an atom of G, and represents (p-iaethansolfinylphenyl) -methylene, and

R2 indica ogni volta idrogeno, ed R3 ed ed R5 indipendentemente uno dall'altro rappresentano idra R2 indicates hydrogen each time, and R3 and and R5 independently of each other represent hydra

gemo, un radicale alifatico, oppure due dei radicali R3, R4 ed R5 rappresentano insieme un radicale alifetico bivalente, insostituito oppure sostituito o interrotto tramite aza, ossa oppure t?a, con la condizione che almeno uno dei radicali R3. R4 ed R5 sia diverso da idrogeno, eventualmente sotto formaci un isomero, accanto agli ausiliari a, oppure additivi usuali per l'applicazione topica, procedimento per la loro produzione, nuovi eomposti della formula I e procedim?nto per la loro pro duzione. gemo, an aliphatic radical, or two of the radicals R3, R4 and R5 together represent a bivalent aliphetic radical, either substituted or substituted or interrupted by aza, bones or t? a, with the condition that at least one of the radicals R3. R4 and R5 is different from hydrogen, optionally under form an isomer, alongside the auxiliaries a, or additives usual for topical application, process for their production, new compounds of formula I and process for their production.

I composti della formula I sono adatti come entiinfiammatori e, oppure analgesici applicabili in modo topico. The compounds of formula I are suitable as inflammatory agents and / or topically applicable analgesics.

DESCRIZIONE DESCRIPTION

L'invenzione riguarda preparati farmaceutici applicabili in modo topico, contenenti sali di acidi alcancarbossilici, in particolare composti della formula The invention relates to topically applicable pharmaceutical preparations, containing salts of alkanecarboxylic acids, in particular compounds of the formula

(I) (THE)

in cui R^ rappresenta un gruppo della formula where R ^ represents a group of the formula

(Ila) (Ila)

nella quale X1 ed X2 indicano idrogeno ed X3 indica isobutile, oppure X1 ed X3rappresentano idrogeno ed X2 rappresenta benzoile, oppure X1 indica idrogeno,, X2 iodica cloro ed X3 ?ndica 3-pirrolin-1-ile, oppure X1 rappresenta idrogeno* ? rappresenta un gruppo del la formula ed X3 insieme con X4 rappresenta un legame* ed R2 indica ogni volta metile, oppure nella quale X2 ed X3 rappresentano idrogeno ed X1 rappresenta 2,6-dicloro~anilino* ed R2 indica idrogeno, oppure nella quale indica un gruppo della formula in which X1 and X2 indicate hydrogen and X3 indicates isobutyl, or X1 and X3 represent hydrogen and X2 represents benzoyl, or X1 indicates hydrogen, X2 iodine chlorine and X3? ndic 3-pyrrolin-1-yl, or X1 represents hydrogen *? represents a group of the formula and X3 together with X4 represents a bond * and R2 indicates methyl each time, or in which X2 and X3 represent hydrogen and X1 represents 2,6-dichloro ~ aniline * and R2 indicates hydrogen, or in which it indicates a group of the formula

(IIb) (IIb)

nella quale X5 rappresenta il legame in comune con il gruppo metin?co nella formula I, X6 od X7 indi ceno idrogeno, X8 rappresenta p-aetil-benzoile, Y ? un atomo di azoto, ad X9 ?ndica un gruppo metili co, oppure nella quale ? un gruppo metilico, rappresenta un legame in comune con il gruppo seti nico nella formula I, X7 indica un gruppo della for mula X8 insieme con X10 rap presenta un legame, Y ? un atomo di azoto ed X9 in dica p-clorobenzoile, oppure nella quale X5? un gruppo metilico, X6 rappresenta il legame in eosm ne con il gruppo met?nico nella formula I, X7 indi, ea un gruppo della formula Z8 insieme con X11 indica un legame, X ? un atomo di C, ed X9 rappresenta (p^raetansolfinilf?sii)~metllene, ed R2 indica ogni volta idrogeno, ed in cui R3, ed R5, indipendentemente uno dall'altro, rappresfp tane idrogeno, un radicale alifatico* oppure due dei radicali R3, R4 ed rappresentano insieme un radicale alifatieo bivalente, insostituito o so?ti tuito od interrotto tramite aza, ossa oppure tia, con la condizione elle almeno uno dei radicali R3, R4 ed sia diverso da idrogeno, eventualmente sot to forma di un isomero, accanto agli ausiliari e, oppure additivi usuali per la applicazione topica, l'impiego di composti della formula I come antiinfiammatori e, oppure analgesici applicabili in modo topico, nuovi composti della formula I e pr? cedimento per la loro produzione. in which X5 represents the bond in common with the methyl group in the formula I, X6 or X7 indi ceno hydrogen, X8 represents p-aethyl-benzoyl, Y? a nitrogen atom, at X9 indicates a methyl group, or in which? a methyl group, represents a bond in common with the setin group in formula I, X7 indicates a group of the formula X8 together with X10 represents a bond, Y? a nitrogen atom and X9 in dica p-chlorobenzoyl, or in which X5? a methyl group, X6 represents the bond in eosm ne with the methyl group in the formula I, X7 indi, and to a group of the formula Z8 together with X11 indicates a bond, X? an atom of C, and X9 represents (p ^ raetansolfinylf? sii) ~ methylene, and R2 each time indicates hydrogen, and in which R3, and R5, independently of each other, represent hydrogen, an aliphatic radical * or two of the radicals R3, R4 and together represent a divalent aliphatic radical, unsubstituted or substituted or interrupted by aza, bones or thia, with the condition that at least one of the radicals R3, R4 is different from hydrogen, possibly in the form of a isomer, alongside the auxiliaries and / or additives usual for topical application, the use of compounds of formula I as anti-inflammatory and, or topically applicable analgesics, new compounds of formula I and pr? subsidence for their production.

Con preparati farmaceutici applicabili in modo topico sono da intendere in particolare quelli nei quali la sostanza attiva ? presente in una forma assorbibile dalla pelle, per esempio insieme con gli ausiliari e, oppure additivi usuali per la ap plicazione topica. With topically applicable pharmaceutical preparations are meant in particular those in which the active substance? present in a form absorbable by the skin, for example together with the auxiliaries and / or additives usual for topical application.

Un radicale alifatico R3, R4 od indica anzitut to un radicale inf.alchilico insostituito od eventualmente sostituito con amiaino, con un gruppo della formula An aliphatic radical R3, R4 or d indicates first of all an unsubstituted lower alkyl radical or possibly substituted with amiaino, with a group of the formula

con ossidrile. (Tali radicali sono per esempio Infoalchile, ammino-inf .alchile, idrossi-inf.alchile oppure oligoidrossi-inf. alchile . with hydroxyl. (Such radicals are for example Infoalkyl, amino-lower alkyl, hydroxy-lower alkyl or oligohydroxy-lower alkyl.

Con un radicale alifatieo bivalente ? da intgn dere ad esempio inf .alchilene a 4 fino a 7 membri, mentre un radicale alifatieo bivalente, interrotto da aza eventualmente sostituito oppure da ossa o da tia, indica per esempio 3-aza-, 3-ossa- oppure 3-tiainf .alchilene a 4 fino a 7 membri, 1? cui aza pu? essere per esempio sostituito con inf.alchile. With a divalent aliphatic radical? to include for example 4- to 7-membered lower alkylene, while a divalent aliphatic radical, interrupted by aza possibly substituted or by bones or thia, indicates for example 3-aza-, 3-oxa- or 3-thiainf. alkylene with 4 to 7 members, 1? which aza pu? be substituted for example with lower alkyl.

In precedenza ed in appresso, con radicali e composti organici designati con "inferiore0 sono da intendere gasili che contengono fino a 7 incluso, anzitutto fino a 4 incluso atomi di C. Previously and hereafter, with radicals and organic compounds designated with "lower 0, gasyls containing up to 7 inclusive, first of all up to 4 inclusive of C atoms are to be understood.

Le definizioni generali impiegate nell*ambito del presente testo hanno anzitutto i seguenti significati: The general definitions used in this text have first of all the following meanings:

I composti della formula CIHa) The compounds of the formula CIHa)

o loro sali sono noti.Questi composti o rispettila mente loro sali con basi vengono impiegati per esem pio come antiinf?ammatori non steroidici nel trattja mento di processi infiammatori. In tal caso ? corri spendenti preparati vendono somministrati prevalentemente per via orale, inoltre .enterale oppure parenterale, per? nel modo di applioazione sono de osservare effetti secondari, anzitutto nella regio ne gastrointestinale, per esempio formazione di ul cera sulle mucose del tratto gastrointestinale, Lo scopo del trattamento d? forme differenti di malattie infiammatorie, in particolare del "reumatismo delle parti molli", risiede di aggirare ampiamente effetti secondari legati prevalentemente alla tera pia sistemica. Per questo ? disponibile anzitutto una terapia t?pica quando si riesce a garantire il trasporto della sostanza attive nella regione di infiammazione, li successo di una terapia mediante applicazione per via cutanea fallisce per? spesso per il fatto che,nell'impiego di sostanze attive della formula (IIIa),si riesce solo insufficientemente a far passare attraverso la pelle, nel tesso to malato. la sostanza attiva in quantit? terapeuticemente efficace. or their salts are known. These compounds or their salts with bases are used, for example, as non-steroidal anti-inflammatories in the treatment of inflammatory processes. Then ? run spending preparations are mainly administered orally, in addition, internally or parenterally, for? in the method of application secondary effects are to be observed, first of all in the gastrointestinal region, for example the formation of ulcer on the mucous membranes of the gastrointestinal tract. different forms of inflammatory diseases, in particular the "rheumatism of the soft parts", lies in largely circumventing secondary effects mainly linked to systemic therapy. Because of this ? first of all is a therapeutic therapy available when it is possible to guarantee the transport of the active substance in the inflammation region, the success of a therapy by means of skin application fails for? often due to the fact that, in the use of active substances of the formula (IIIa), it is only insufficiently possible to pass through the skin, into the diseased tissue. the active substance in quantity? therapeutically effective.

A base dell?invenzione sta la constatazione sor prendente che i composti della formula (I) si dist?nguono per eccellenti propriet? di penetrazione ed assorbimento percutanei. At the basis of the invention is the surprising observation that the compounds of formula (I) are distinguished by excellent properties. percutaneous penetration and absorption.

Inoltre i composti della formula (I)da sdogo rare secondo l?invenzione hanno precipue proprie t? antiinfiammatorie ed analgesiche. L?efficacia enti, infiammatoria si lascia dimostrare sul ratto per esempio in base alla netta riduzione del r?goafiamen te della zampa del ratto nei modello dell?edema di zampa da caolino, prodotto secondo Helv. Pesici . Furthermore, the compounds of formula (I) to be tested according to the invention have their own principal t? anti-inflammatory and analgesic. The inflammatory effect can be demonstrated on the rat, for example, on the basis of the net reduction of the rat paw inflammation in the model of kaolin paw edema, produced according to Helv. Pesici.

Acta 156 (1967), in cui ad esempio un gel, cog. tenente circa 0,5 fino a 5% della sostanza attiva, viene introdotto mediante massaggio nella pelle dorsale rasata degli animali di prova. (Letteratura: Arzneimittel-Forsehung 27 (I), 1326 (1977)). Inol tre l'attivit? antiinfiammator?a di applicazione topiea della sostanza attiva? per esempio sotto forma di un gel contenente circa 0,5 fino a 5% della sostanza attiva, pu? venire derivata dalla inibizione di una formazione di ascesso che viene provocata nel ratto mediante iniezione sotto-cutanea di earragenina (letteratura: Arzneim. Fcrsch. 27(1)? 1326, 1977). Acta 156 (1967), in which for example a gel, cog. containing about 0.5 to 5% of the active substance, it is introduced by massage into the shaved dorsal skin of the test animals. (Literature: Arzneimittel-Maybehung 27 (I), 1326 (1977)). In addition, the activity? anti-inflammatory by topical application of the active substance? for example in the form of a gel containing about 0.5 to 5% of the active substance, can? derived from the inhibition of an abscess formation that is caused in the rat by subcutaneous injection of earragenin (literature: Arzneim. Fcrsch. 27 (1)? 1326, 1977).

Esami di composti della formula I sul modello del saggio di Vr?thing con fenil-p-benzochinone (Me todica: J. Pharmacol. exp, Therap. 125. 237, 1959} nel campo di dosaggio di circa 0,1 fino a circa 120 mg per via orale,indicano una n?tta efficacia analgesica . Tests of compounds of formula I on the model of the Vr? Thing assay with phenyl-p-benzoquinone (Method: J. Pharmacol. Exp, Therap. 125. 237, 1959} in the dosage range from about 0.1 to about 120 mg orally indicate a strong analgesic efficacy.

I composti della formula I sono quindi adatti eccellentemente coste ant?inf?aimaator? adoperabili per via cutanea, inoltre sono adoperabili come analgesici. The compounds of the formula I are therefore excellently suited ribs ant? Inf? Aimaator? They can be used through the skin and can also be used as analgesics.

L'invenzione riguarda in particolare prepara ti farmaceutici adoperabili per via topica, contenenti un composto della formula I, in cui ed R2 hanno i significati indicati all'inizio, The invention relates in particular to pharmaceutical preparations which can be used topically, containing a compound of the formula I, in which and R2 have the meanings indicated at the beginning,

R R4 ed R5 indipendentemente fra loro, rapp?e sentano idrogeno, un radicale inf..olchilico insostituito oppure sostituito con amraiao, con un gruppo della formula R R4 and R5 independently of each other, represent hydrogen, an unsubstituted lower-alkyl radical or substituted with amraiao, with a group of the formula

o con ossidrile, oppure,due dei radicali or with hydroxyl, or, two of the radicals

R R4 ed R5 indicano inf. loh?lene a 4 fino a 7 membri, oppure inf.alehilene a 4-fino a 7 mem bri, interrotto mediante aza contenente eventoal mente inf.alchile o mediante ossa oppure tia, con la condizione che almeno uno dei radicali R4 ed R5 sia diverso da idrogeno, nonch? l'impiego di questi composti come antiinflaminatori e, oppure analgesici adoperabili in modo topico. R R4 and R5 indicate inf. 4 to 7 membered loh? lene, or 4 to 7 membered inf.alehylene, interrupted by aza containing possibly lower alkyl or by bone or thia, provided that at least one of the radicals R4 and R5 is other than hydrogen, as well as? the use of these compounds as anti-inflammatory and / or topical analgesics.

Fra essi rientrano per esempio preparati farmaceutici adoperabili in modo topico, contenenti un composto della formula I, in cui R1 ed R2 hanno i significati indicati all-iniaio, ed ?,, B4 nonch? R5 indipendentemente l'uno dall'altro rappresentano idrogeno, inf.alchile, ammino-inf.alchile, inf.alchile sostituito con un gruppo della formula They include, for example, pharmaceutical preparations which can be used topically, containing a compound of the formula I, in which R1 and R2 have the meanings indicated in steel, and?, B4 as well as? R5 independently of each other represent hydrogen, lower alkyl, amino-lower alkyl, lower alkyl substituted with a group of the formula

i?rossi-inf .elc hile, oligoidrossi-inf.clehile, oppure due dei radicali R3, ed R4 indicano inf?-alchilene a 4 fino a 7 membri oppure inf.alchilene a 4 fino a 7 membri interrotto d? aza eventualmente N-inf .alchilato oppure da ossa o da tia. L'invenzio ne riguarda anzitutto preparati farmaeeutiei adoperabili in modo topico, contenenti un composto della formula I, in cui R1 ed R2 hanno i significati in?i eati all'inizio, ed R3, R4 ed R5 indipendentemente l'uno dall'altro indicano inf.alehile eon fino a 4 incluso atomi di C, come metile od etile, oppure idrossi-inf . lebile con fino a 4 incluso atomi di C, sose 2-idross?etile? oppure uno dei radicali the? red-lower-alkyl, oligohydroxy-lower-clyl, or two of the radicals R3, and R4 indicate 4- to 7-membered lower-alkylene or 4- to 7-membered lower alkylene interrupted d? aza possibly N-lower alkylate or from bone or thia. The invention first of all concerns pharmaceutical preparations which can be used topically, containing a compound of the formula I, in which R1 and R2 have the meanings in? I and ati at the beginning, and R3, R4 and R5 independently of each other indicate inf.alehile up to 4 inclusive C atoms, such as methyl or ethyl, or hydroxy-inf. lebile with up to 4 inclusive atoms of C, sose 2-hydroxy? ethyl? or one of the radicals

R4 ed R5 indica idrogeno e gli altri, indipendente mente uno dall?altro, indicano infoflebile con fino a 4 incluso atomi di C,come etile, idrossiinfoalchile con fino a 4 incluso atomi di C, come 2.-idrossi~etile oppure 2-idrossi-propile, oppure insieme indicano inf.alchilene a 4 fina e 7 membri, come 1,4-butilene oppure l,5~pentilene, azaeventualmente N-inf.alchilato oppure ossa- oppure tia?infcalchilene a 4 fino a 7 membri, come 5-aza-3-ossa- oppure 3-tia-l,5-pentilene, oppure .uno degli altri indica inf.alchile con fino 4 incluso atomi di C,come metile, ed il terze indica oligo?drossi-inf. alenile, come 2,3,4,5,6-pentaidrossi-1-esile derivante da P-glucammina, oppure due.dei radicali R3, R4 ed R5rappresentano idrogeno e l'al tre rappresenta inf.alchile con fino a 4 incluso atomi di C,cosic etile, ?drossi-inf.alchile con fino a 4 incluso atomi di C,cerne 2-idrossi-etile, oligo-idrossi-inf calchile con fino a 4 inel?so atomi di C,come tris-(idrossimetil)~metile, ammainoinf calchile con fino a 4 incluso atomi di C,come 2 -emminoetile, od un gruppo della formula R4 and R5 indicate hydrogen and the others, independently of each other, indicate infofleble with up to 4 including C atoms, such as ethyl, hydroxyinfoalkyl with up to 4 including C atoms, such as 2-hydroxy ~ ethyl or 2- hydroxy-propyl, or together they indicate 4-membered and 7-membered lower alkylene, such as 1,4-butylene or 1,5-pentylene, possibly N-lower alkylate or 4- to 7-membered oxa- or thia? infalkylene, such as 5-aza-3-oxa- or 3-thia-1,5-pentylene, or one of the others indicates lower alkyl with up to 4 including C atoms, such as methyl, and the third indicates oligo? droxy-lower. alkyl, such as 2,3,4,5,6-pentahydroxy-1-hexyl derived from P-glucamine, or two of the radicals R3, R4 and R5 represent hydrogen and the other represents lower alkyl with up to 4 atoms included of C, soicethyl,? hydroxy-lower alkyl with up to 4 including C atoms, cerne 2-hydroxy-ethyl, oligo-hydroxy-inf calkyl with up to 4 inel? or C atoms, such as tris- (hydroxymethyl ) ~ methyl, ammainoinf calkyl with up to 4 inclusive C atoms, such as 2 -eminoethyl, or a group of the formula

eelle.Quale alk indica inf.alchilene con fino a 4-incluso atomi di C come etilene, nonch? l'impiego eelle.What alk indicates lower alkylene with up to 4-inclusive C atoms such as ethylene, as well as? employment

di Questi composti come antiinfiammatori e, oppure analgesici impiegabili in modo topico? of these compounds as anti-inflammatory and / or analgesics that can be used topically?

L 'invenzione riguarda anzitutto preparati farmaceutici adoperabili in modo topico, contenenti The invention first of all relates to topically usable pharmaceutical preparations containing

un composto della formula I, in cui R indica un gruppo della formala (Ila) nella Quale rappresenta idrogeno, X rappresenta un gruppo della a compound of the formula I, in which R indicates a group of the formala (IIa) in which represents hydrogen, X represents a group of the

formula ,ed X3 insieme con X4 rappresenta un legame, ed R2 ? metile, oppure in formula, and X3 together with X4 represents a bond, and R2? methyl, or in

cui R indica un gruppo della formula (IIa) nella quale ? 2,6-d?eloroaailino, X2 ed X3 rappres?n which R indicates a group of the formula (IIa) in which? 2,6-d? Eloroaailino, X2 and X3 represent? N

taso idrogeno, ed R2 ? idrogeno, oppure in cui so hydrogen, and R2? hydrogen, or in which

indica un gruppo della formula (Ilb), nella quale indicates a group of the formula (Ilb), in which

X5 ? un gruppo met?lico, X6 rappresenta Un legame X5? a metal group, X6 represents A bond

in comune con il gruppo metinico della formula 1, in common with the methine group of formula 1,

?7 indica un gruppo della formula ? 7 indicates a group of the formula

? insieme con rappresenta un legame, Y ? un ? together with represents a bond, Y? a

atomo di azoto ed X9 indica p-clorobenzo?le, ed nitrogen atom and X9 indicates p-chlorobenzo? le, ed

? idrogeno, ed R3, R4 ed R5 hanno i significati immediatamente precedenti, nonch? l?impiego di que ? hydrogen, and R3, R4 and R5 have the immediately preceding meanings, as well as? the use of that

sti composti coma antiinfiammtori e, oppure anal-, gasici adoperabili in modo topico? Are these compounds as anti-inflammatory and, or anal-, gasic compounds that can be used topically?

L'invenzione riguarda in primissima linea pie parati farmaceutici adoperabili in modo topico, contenenti un composto della formula I, in cui ed hanno 1 significati immediatamente preceder! ti,ed R3 ed R4 nonch? R5 indicano idrossi-inf.-alchile con fino a 4 incluso atomi di C come The invention relates in the very first line to topically usable pharmaceutical cakes containing a compound of formula I, wherein and have the meanings immediately preceding it. you, and R3 and R4 as well? R5 denote hydroxy-lower-alkyl with up to 4 inclusive C atoms such as

2-idrossietile, oppure uno dei radicali R3, ed R5 indica idrogeno e gli altri indicano inf?-alchile con fino a 4 incluso atomi di come ?ti le, idrossi-inf-alchile con fino a 4 incluso ato ai di C, come 2-idrossi-etile, oppure ossa?nf alchilsne a 4 fino a 7 membri,come 3-ossa-l,5-pentilene, nonch? l'impiego di questi composti come antiinfiammatori e, oppure analgesici adopera, bili in modo topico? 2-hydroxyethyl, or one of the radicals R3, and R5 denotes hydrogen and the others denote inf? -Alkyl with up to 4 including atoms of as? Ti le, hydroxy-inf-alkyl with up to 4 including atoms of C, as 2-hydroxy-ethyl, or oxo? Nf alkylsne with 4 to 7 members, such as 3-oxo-1,5-pentylene, as well as? the use of these compounds as anti-inflammatory and, or analgesics, can be used topically?

L'intenzione riguarda preferibilmente prepara ti farmaceutici adoperabili in m?do topico, conte nenti un composto della formula I, in cui indica un grupo della formula Ila nella quale rap presenta 2,6-dicloroanalino ed X2 ed rappresentato idrogeno, ed R ? idrogeno,ed R3, R4 ed R5 hanno i significati indicati in precedenza, nonch? l'impiego d? qu?sti composti come antiinfiammatori e, oppure analgesici adoperabili in modo topico? Particolarmente preferiti sono preparati far maceutici adoperabili in modo topico, contenenti un composto della formula I, in cui R1 ed R2The intention preferably relates to pharmaceutical preparations usable in topical mode, containing a compound of the formula I, in which it indicates a group of the formula IIa in which represents 2,6-dichloroanalino and X2 and represented hydrogen, and R? hydrogen, and R3, R4 and R5 have the meanings indicated above, as well as? the use d? these compounds as anti-inflammatories and, or topically used analgesics? Particularly preferred are pharmaceutical preparations which can be used topically, containing a compound of the formula I, in which R1 and R2

i significati nominati immediatamente in precedenza ed uno dei radicali R3, R4 ed R5 indica idrogeno e gli altri indicano inf.alchile con fino a 4 incluso atomi di C,come etile, oppure 3-ossa-inf.alchilene a 4 fino a 7 m?mbri,come 3-ossa~l,5~pentitene, non ch? l'impiego d? questi composti come antiinfiamma tori e, oppure analgesici adoperabili in modo topico. the meanings mentioned immediately above and one of the radicals R3, R4 and R5 indicates hydrogen and the others indicate lower alkyl with up to 4 including C atoms, such as ethyl, or 3-bone-lower alkylene at 4 to 7 m ? mbri, like 3-bones ~ l, 5 ~ regret it, not ch? the use d? these compounds as anti-inflammatories and / or topically usable analgesics.

L'invenzione riguarda specialmente i preparati farmaceutici adoperabili in modo topico, nominati negli esempi, e rispettivamente 1,impiego di questi composti come anti?nfiammatori e, oppure anni gasici adoperabili in modo topico? The invention especially relates to the topically usable pharmaceutical preparations, named in the examples, and 1 respectively, to the use of these compounds as anti-inflammatories and / or gas years which can be used topically.

L'invenzione riguarda inoltre un procedimento per la produzione di preparati farmaceutici appli cabili in modo topico. Il procedimento ? caratterizzato da ci? che uno dei composti della formula The invention also relates to a process for the production of topically applicable pharmaceutical preparations. The procedure? characterized by there? than one of the compounds of the formula

I nominati in precedenza viene mescolato con ausiliari e, oppure additivi usuali per l'applicazione topica. The aforementioned is mixed with auxiliaries and / or additives usual for topical application.

L'invenzione riguarda inoltre nuovi composti della formula I, in cui indica un gruppo della formula Ila nella quale X1 indica idrogeno, rap presenta un gruppo della formula The invention also relates to new compounds of the formula I, in which it indicates a group of the formula IIa in which X1 indicates hydrogen, represents a group of the formula

ed X3 insieme con ? indica un legame, R2 ? metile , ed R3 ad nonch? R4 rappresentano etile oppure 2~idxossi~etile, oppure uno dei radicali R3, ed R5 rappresenta idrogeno e gli altri rappresentano etile, R-?drossi-etile oppure 3-ossa-l,5-pentilene, oppure in cui Ri ? un gruppo della formula Ha nel la quale X1 indica 2,6-dicloroanilino? X2 ed X3 in~ dicano idrogeno. R2 ? idrogeno ed uno dei radicali R3, R4 nonch? R5 rappresenta idrogeno e gli altri rappresentano etile, oppure i radicali R4 ed R5 indicano ogni volta 2-idrossi~et?le, oppure ih cui ? oo gruppo della formula IIb nella quale X5 indica metile, X6 rappresenta un legame la comune con il gruppo metiniee della formula I, X9 ? un gruppo della formula X8 insieme con X10 indica un legame, T ? un atomo di aaoto e Xq rappresenta p-clorobenzo?le. R2 indica idrogeno, ed R3, R4 nonch? R5 indicano idrossiinfcalchile con fino a 4 incluso atomi di C,come 2~idrossietile , oppure etile, oppure due dei radicali R3, R4 ed R5 rappresentano idrossi-inf.-alchile con fino a 4 incluso atomi d? G,come and X3 together with? indicates a bond, R2? methyl, and R3 ad as well? R4 represent ethyl or 2-idoxy-ethyl, or one of the radicals R3, and R5 represents hydrogen and the others represent ethyl, R-? Hydroxy-ethyl or 3-oxo-1,5-pentylene, or in which Ri? a group of the formula Ha in which X1 indicates 2,6-dichloroanilino? X2 and X3 denote hydrogen. R2? hydrogen and one of the radicals R3, R4 as well as? R5 represents hydrogen and the others represent ethyl, or the radicals R4 and R5 each time indicate 2-hydroxy age, or which? oo group of formula IIb in which X5 indicates methyl, X6 represents a common bond with the methyniee group of formula I, X9? a group of the formula X8 together with X10 indicates a bond, T? an atom of aaoto and Xq represents p-chlorobenzo? le. R2 indicates hydrogen, and R3, R4 as well as? R5 denote hydroxy alkyl with up to 4 inclusive C atoms, such as 2 ~ hydroxyethyl, or ethyl, or two of the radicals R3, R4 and R5 represent hydroxy-lower-alkyl with up to 4 inclusive d atoms. G, like

2-idrossietiie, oppure etile, e l'altro ? idrogeno, oppure uno dei radicali R3, R4 ed R5 indica idross?-inf .alchile con fino a 4 incluso atomi di C,come 2-?drossi-etiie,eppure etile,e gli altri indicano idrogeno( od un isomero di essi, il loro impiego, preparati farmaceutici eh? li contengono nonch? procedimenti per la loro produzione? 2-hydroxieties, or ethyl, and the other? hydrogen, or one of the radicals R3, R4 and R5 indicates hydroxy? -inf .alkyl with up to 4 including C atoms, such as 2-? hydroxyethyl, yet ethyl, and the others indicate hydrogen (or an isomer thereof, their use, pharmaceutical preparations eh? they contain them as well as processes for their production?

L 'invenzione riguarda inoltre nuovi composti della formula I, in partieoiaire quei composti in cui R1 indica ?a gruppo delle formula Ila polla quale indica idrogen?, X2 rappresenta un gruppo della formula ed X3 insieme con indica un legame, R ? metile,ed R3 R4 ch? R5 rappresentano etile oppure 2-idrossietile, oppure uno dei radicali R3, R4 ed R5 rappresenta idrogeno e gli altri rappresentano etile, 2-idrossietile oppure 3ossa~l,5~pent?l?ne. The invention also relates to new compounds of formula I, in particular those compounds in which R1 indicates? A group of formula II, which indicates hydrogen ?, X2 represents a group of the formula and X3 together with indicates a bond, R? methyl, and R3 R4 ch? R5 represent ethyl or 2-hydroxyethyl, or one of the radicals R3, R4 and R5 represents hydrogen and the others represent ethyl, 2-hydroxyethyl or 3oxy-1,5-pent? L? Ne.

L'invenzione riguarda inoltre nuovi composti del la formula I, in particolare quei composti in cui ? ?a gruppo della formula Ila nella quale .indica 2,6-dicloro-anilino, X2 X3 indicano idroge no, R ? idrogeno,ed uno dei radicali R3 R4ch? R5 rappresenta idrogeno e gii altri rappresentano etile, oppure i radicali R3, R4 ed R5 indicano The invention also relates to new compounds of the formula I, in particular those compounds in which? ? a group of formula 11a in which indicates 2,6-dichloro-aniline, X2 X3 indicate hydroge no, R? hydrogen, and one of the radicals R3 R4ch? R5 represents hydrogen and the others represent ethyl, or the radicals R3, R4 and R5 indicate

2-idrossiet ile. 2-hydroxyethyl.

L'invenzione riguarda inoltre nuovi composti della formula I, in particolare quelli nei quali R1 rappresenta un gruppo della formula Ib nella X5 indica setile, X6 rappresenta un legame in co mune con il gruppo metanico della formula I, ? un gruppo della formula X8 insieme con X10 , ?ndica mi legame, Y ? un atomo di azoto ed rappresena p-clorobenzoile. R indica idrogeno, ed R3, R4 nonch? R5 indicano idrossiinf.alchile con ino a. 4 incluso atomi di C,come 2-idrossietile .oppure etile, eppure due dei radicali R3, R4 ed R5 rappresentano idrossi-inf.-alchile con fino a 4 incluso atomi di C come The invention also relates to new compounds of formula I, in particular those in which R1 represents a group of formula Ib in X5 indicates setyl, X6 represents a bond in common with the methane group of formula I,? a group of the formula X8 together with X10,? ndica me bind, Y? a nitrogen atom and represents p-chlorobenzoyl. R indicates hydrogen, and R3, R4 as well as? R5 denote hydroxy-lower alkyl with ino a. 4 including C atoms, such as 2-hydroxyethyl or ethyl, yet two of the radicals R3, R4 and R5 represent hydroxy-lower-alkyl with up to 4 including C atoms as

2-idrossi-etile , oppure etile, e l?altro ? idrogg no, oppure uno dei radicali R3, R4 ed R5 indica idrossi inf.alchile con fino a 4 incluso atomi di C, come 2 -idroasietile, oppure etile, e gli altri indicano idrogeno. 2-hydroxy-ethyl, or ethyl, and the other? hydroxy, or one of the radicals R3, R4 and R5 indicates hydroxy lower alkyl with up to 4 including C atoms, such as 2-hydroxyethyl, or ethyl, and the others indicate hydrogen.

L'? invenzione riguarda specialmente i nuovi composti ottenibil secondo gli esempi nonch? procedimenti di produzione ivi descritti. L'? invention especially concerns the new compounds obtainable according to the examples as well as production processes described therein.

I composti della formula I possono presentar si ciascuno, secondo scelta delle sostanze d? p?r tenza e modi di lavorazione, sotto f?rma di un isomero possibile e di ima miscela di questi, per esempio come isomeri ottici, come enant?omeri oppure diastereomeri, oppure isomeri geometrici come cis- rans-isoaeri .In tal caso, gli isomeri ot tici sono presenti sotto forma degli antipodi puri e, oppure come racemati. Racemat? o miscugli di isomeri geometrici ottenuti possono venire separati nei costituenti puri in base a differenze chimi co-f?siche dei coronanti. Cosi ad esempio raeemati di antipodi ottici possono venire separati nei corrispondenti ant?meri secondo metodi di per s? noti, per esempio per mezzo di processo eromatogra fico, mediante cristallizzazione frazionata, microorganismi oppure enzimi? Inoltre ad esempio antipodi ottici possono venire arricchiti in un miscuglio raceraiee mediante conversione dell'altro antimero. vantaggiosamente si isola il pi?.efficace degli isomeri che entrano in considerazione? Gli isomeri di nuovi composti della formula I formano parimenti oggetto dell'invenzione. The compounds of the formula I can be present each, according to the choice of the substances d? power and processing methods, under the sign of a possible isomer and a mixture of these, for example as optical isomers, such as enanthomers or diastereomers, or geometric isomers such as cis-rans-isoaers. , the optical isomers are present in the form of the pure antipodes and / or as racemates. Racemat? or mixtures of geometric isomers obtained can be separated into the pure constituents on the basis of chemical and physical differences of the coronants. Thus, for example, rows of optical antipodes can be separated into the corresponding antimers according to methods per se. do you notice, for example by means of an eromatographic process, by means of fractional crystallization, microorganisms or enzymes? Furthermore, for example, optical antipodes can be enriched in a racial mixture by conversion of the other antimer. advantageously the most effective of the isomers that come into consideration is isolated. The isomers of new compounds of formula I also form the subject of the invention.

I composti della formula I possono venire ottenuti anche sotto forma dei loro idrati eppure includere anche solventi adoperati per la cristallizzazione . The compounds of formula I can also be obtained in the form of their hydrates and yet also include solvents used for crystallization.

Oggetto dell 'invenzione sono inoltre proc?di menti per la produzione dei nuovi composti della formula I i Quali vengono preparati secondo moto di di per s? noti. Object of the invention are also processes for the production of the new compounds of the formula I. Which are prepared according to their own motion. known.

Una variante preferita di procedimento ? carat terizzata per esempio da ci? che un acido cartocci lico organico della formula A preferred variant of the procedure? characterized for example by there? than an organic foil of the formula

(IIIa) (IIIa)

.,; .,;

oppure un suo sale,basico differente da un stale della formula I viene fatto reagire con una quantit? almeno equimolare dell'em ina della formula or a salt thereof, basic different from a stal of the formula I is reacted with a quantity? at least equimolar of the em ina of the formula

(IIIb) (IIIb)

o con un suo sale di addizione con acido e, se desiderato, un composto della formula I ottenibile secondo il procedimento viene trasformato in un al tro composto della formula I e, oppure un miscuglio di isomeri ottenibile secondo il procedimento viene separato nei componenti. or with an acid addition salt thereof and, if desired, a compound of formula I obtainable according to the process is transformed into another compound of formula I and, or a mixture of isomers obtainable according to the process is separated into the components.

Il rapport? molare.di acidi della formula IIIa e di am ine della formula IIIb dipende dalla scelta dei sali desiderati,rispettivamente dal numero degli amminogruppi sostituiti nel corrispondente eota posto della formula IIIb. The rapport? molar of acids of formula IIIa and of amine of formula IIIb depends on the choice of the desired salts, respectively on the number of amino groups substituted in the corresponding element of formula IIIb.

Come sali di addizione con acido di stamine del la formula IIib vengono impiegati per esempio corrispondenti idroalogenuri,come"cloridrati* Corresponding hydrohalides, such as "hydrochlorides *, are used as the acid addition salts of the formula IIib, for example.

La reazione di composti della formula Illa con composti della formula IIIb ha luogo vantaggiosamente la un solvente o rispettivamente diluente inerte, se necessario con raffreddamento e riscal d amento, per esempio in un campo di temperature di circa 0? fino e circa 100 ?C, preferibilmente a temperatura ambiente, in un recipiente chiuso e, oppiare sotto atmosfera di gas inerte, per esempie azoto . The reaction of compounds of formula IIa with compounds of formula IIIb advantageously takes place in an inert solvent or diluent, if necessary with cooling and heating, for example in a temperature range of about 0? up to about 100 ° C, preferably at room temperature, in a closed vessel and, opiate under an atmosphere of inert gas, for example nitrogen.

Come solventi e diluenti adatti entrano in con siderazione per esempio acqua, alcoli come inf?? aleanoli, per esempio metanolo od etanolo, eteri come eteri di-inf.alcilici , per esempio etere dietilico nonch? eteri ciclici per esempio diqs sano oppure tetraxdrofurano, chetoni come diinf . alchilchetoni , per esempio acetone, esteri di acidi carbossilici coae estere d? acidi inf. alcancarbossilici, per esempio estere etilico di acido acetico, amidi come N,N-diinf,alchil. amidi, per esempio N, N-dimet?lf prmasmide , sol fossidi come di-inf.-alchil-solfossidi , per esem pio dimetilaolf ossidi, oppure miscele di essile sostanze di partenza delle formule Ila e IIIb sono note? As suitable solvents and diluents come into consideration for example water, alcohols such as inf? aleanols, for example methanol or ethanol, ethers such as di-lower alkyl ethers, for example diethyl ether as well as ethers. cyclic ethers e.g. healthy diqs or tetraxdrofuran, ketones such as diinf. alkylketones, for example acetone, esters of carboxylic acids coa and ester d? lower acids alkanecarboxylic, for example ethyl ester of acetic acid, starches such as N, N-diinf, alkyl. starches, for example N, N-dimethylf prmasmide, solids such as di-lower-alkyl-sulfoxides, for example dimethylulfoxides, or mixtures of exile starting substances of the formulas 11a and IIIb are known?

L' invenzione riguarda anche quelle forme di esecuzione del procedimento scendo le quali le so stanze di partenza vengono prodotte in sito, oppure nelle quali una sostanza di partenza viene ricavata pelle condizioni di reazione da un derivato e, oppure viene impiegata sotto forma di un miscuglio di isomeri o di un isomero puro. The invention also relates to those embodiments of the descending process in which the starting substances are produced on site, or in which a starting substance is obtained under reaction conditions from a derivative and, or is used in the form of a mixture. of isomers or of a pure isomer.

I composti di partenza della formula Hla possono venire formati per esempio nelle condizioni di reazione da corrispondenti esteri,come esteri inf. alchilici, mediante idrolisi in presenza di una base come una ammina, per esempio dietilammina. Una ammina della formula IIIb pu? venire impiegata per esempio sotto formad? un sale di addizione con acido, come un idroalogenuro,. per esempio cloridrato, e ve pire messa in libert? in presenza di Una base, come una ammina. The starting compounds of the formula Hla can be formed for example under the reaction conditions from corresponding esters, such as lower esters. alkyls, by hydrolysis in the presence of a base such as an amine, for example diethylamine. An amine of the formula IIIb pu? be used for example under formad? an acid addition salt, such as a hydrohalide,. for example hydrochloride, and pire free? in the presence of a base, such as an amine.

Nel procedimento della presente invenzione vengo no adoperate preferibilmente quelle sostanze di par tenza che conducono a composti particolarmente pregevoli . In the process of the present invention those starting substances which lead to particularly valuable compounds are preferably used.

I preparati farmaceutici secondo 1,invenzione, adoperabili in modo topico, contengono i composti dalla formula I, adoperabili farmaceuticamente, con un materiale aggiuntivo od ausiliario, adope rabile in modo farmaceutico. Il dosaggio giornalie ro della sostanza attiva dipende dalla et? e dallo stato individuale, nonch? dal modo di applicazione. Come preparati farmaceutici adoperabili in sodo topico entrano in considerazione anzitutto creme, pomate e geli, inoltre paste, schiusa, tinture e soluzioni, che contengono circa 0,5 fino a circa The pharmaceutical preparations according to the invention, which can be used topically, contain the compounds of formula I, which can be used pharmaceutically, with an additional or auxiliary material, which can be used pharmaceutically. Does the daily dosage of the active substance depend on the age? and from the individual state, as well as? by way of application. As pharmaceutical preparations that can be used in topical soda, first of all creams, ointments and gels, also pastes, hatching, tinctures and solutions, which contain about 0.5 to about

5% della sostanza attiva? 5% of the active substance?

Creme e lozioni sono emulsioni olio in acqua che presentano pi? di 50% di acqua? Come base eleo sa,s?.adoperano anzitutto alcoli grassi, per esempio alcool laurilico, cotilico oppure sfrearilico, acidi grassi, per esempio acido palmitico oppure stearico, cere liquide fino a solide, per esempie isopropilmiristato, cera di lana oppure cera d'api e, oppure idrocarburi, per esempio vaselina (petroiate) od olio di paraffina? Come emulsionatori entrano in considerazione sostanze tens?oattive con propriet? prevalentemente idrofile, come adatti emulsionatori non ioniei, per esempio esta ri di acidi grassi di pol?aleoli oppure loro addot ti con ossido di etilene, come esteri di acidi grassi di glicerina polimerici oppure esteri di acidi grassi di poliossietilen-sorbifrano (Tweens), inoltre eteri di alcoli grassi od esteri di acidi grassi poliossiet?len?ci oppure corrispondenti emulsionatori ionici, come sali di metalli alcalini di solfati di alcoli grassi, par esempio laurilsoXfato di sodio, cetilsolfate di sodio oppure sto arii solfato di sodio, i quali vengono adoperati usualmente in presenza di aieoli grassi, per esempio alcool cetilieo oppure alcool stear?lieo. Addi ti vi alla fase acquosa sono fra l?altro agenti che impediscono l?asciugamento delle creme, per esempio polialeoli come glicerina, sorbite, propilenglicole e, oppure polietilenglicoli, in?ltre agenti conservanti, sostanze odorose ecc. Creams and lotions are oil-in-water emulsions that have more? of 50% water? As a base, they are used primarily fatty alcohols, for example lauryl, acetyl or sphearylic alcohol, fatty acids, for example palmitic or stearic acid, liquid waxes up to solid, for example isopropyl myristate, wool wax or beeswax. and, or hydrocarbons, for example petroleum jelly (petroiate) or paraffin oil? As emulsifiers, tens? Oactive substances with proprietary properties come into consideration? predominantly hydrophilic, as suitable non-ionic emulsifiers, for example esters of polyoxylic fatty acids or their additives with ethylene oxide, such as esters of polymeric glycerol fatty acids or esters of polyoxyethylene-sorbifran (Tweens) fatty acids, furthermore, ethers of fatty alcohols or esters of polyoxyethylene fatty acids or corresponding ionic emulsifiers, such as alkali metal salts of sulphates of fatty alcohols, for example sodium laurylsoXfate, sodium cetylsulfate or sodium hydroxide, which are usually used in the presence of fatty acids, for example cetyl alcohol or stear? alcohol. Additions to the aqueous phase are, among other things, agents that prevent the creams from drying out, for example polialeols such as glycerin, sorbite, propylene glycol and, or polyethylene glycols, in other preservative agents, odorous substances, etc.

Pomate o lozioni sono emulsioni acqua in olio le quali contengono fino a 70% ma preferibilmente circa 20% fino a circa 50% di aco.ua o di fase acquosa . Come fase grassa entrano in considerazione anzitutto idrocarburi, per esempio vaselina, olio di paraffina e, oppure paraffine dure che per il miglioramento del potere di legare acqua contengo no proferibilmente adatti idrossi-composti c?me alcoli grassi o loro esteri, per esempio alcool cetilieo oppure alcoli di cera di lana o rispettivamente cera di lana. Emulsionatori sono corri spondenti sostanze lipofilo come esteri di acidi grassi di sorbitano (Spana), per es?mpio oleato di sor bitano e, oppure isostearato di sorbitane. Additivi alla fase acquosa sono fra l?altro agenti di trattenuta d? umidit? come pol? alcoli, per esempio glicerina, propilenglieole, e orbite e, oppure pol?etilenglicole, nonch? agenti conserranti, sostanze odorose ecc. Ointments or lotions are water-in-oil emulsions which contain up to 70% but preferably about 20% to about 50% water or aqueous phase. As the fat phase, hydrocarbons are first considered, for example petroleum jelly, paraffin oil and / or hard paraffins which, for the improvement of the power to bind water, contain preferably suitable hydroxy-compounds such as fatty alcohols or their esters, for example cetyl alcohol or alcohols of wool wax or wool wax respectively. Emulsifiers are corresponding lipophilic substances such as esters of sorbitan fatty acids (Spana), for example sorbitane oleate and / or sorbitane isostearate. Additives to the aqueous phase are, among other things, retaining agents d? humidity how pol? alcohols, for example glycerin, propylene glycol, and orbits and, or pol? ethylene glycol, as well as? preservative agents, odorous substances, etc.

Microemulsioni sono sistemi isotropi il cui fondamento ? costituito dai seguenti quattro compo ment? i acqua, un emulsionatore come un tensioattivo, per esempio Eumulgia, un l?pide come un olio non polare, per esempio olio di paraffina, ed un alcool con un gruppo lipofilo, per esempio 2-ottildodecanolo. Se lo si desidera, le meroemulsioni possono venire addizionate di altri additivi. Microemulsions are isotropic systems whose foundation? consisting of the following four compo ment? water, an emulsifier such as a surfactant, for example Eumulgia, a l? pide such as a non-polar oil, for example paraffin oil, and an alcohol with a lipophilic group, for example 2-octyldodecanol. If desired, the meroemulsions can be added with other additives.

Pomato grasse sono anidre e contengono come fon demento in particolare idrocarburi, per esempio paraffina, vaselina e, oppure paraffine liquide, inol tre grasso naturale o parzialmente sintetico, per esempio tr?gliceride di acido grasso d? cocco, o pre feribilmente olii induriti, per esempio elio di ara chidi o di ricino idrogenato, inoltre esteri parzia li di acidi grassi della glicerina per esempio mono- e di sterrato di glicerina, nonch? per esempio gli alcoli grassi, emulsionatori e, oppure additivi che aumentano la capacit? di assorbimento d'acqua, menzionati in relazione alle pomate. Fatty tomatoes are anhydrous and contain in particular hydrocarbons as a source, for example paraffin, petroleum jelly and / or liquid paraffins, in addition natural or partially synthetic fat, for example tr? Glyceride of fatty acid d? coconut, or preferably hardened oils, for example helium of arachids or hydrogenated castor, in addition partial esters of glycerin fatty acids, for example mono- and sterrate of glycerin, as well as glycerin mono- and sterrate esters. for example, fatty alcohols, emulsifiers and, or additives that increase the capacity? of water absorption, mentioned in connection with ointments.

Ne? casi dei geli si distingue fra geli acquosi. Neither? cases of frosts one distinguishes between watery frosts.

anidri o poveri di acqua, i quali sono costituiti da materiali rigonfiabili, formaati gel. In primo luogo giungono all ' impiego idrogeli trasparenti a base di macromolecole inorganiche od organiche. Comonenti inorganici macromolecolari con proprie t? di formazione di gol sono prevalentemente siliceti acquosi come silicati di alluminio, per esempio bentonite, silicati di magnesio-alluminio- per esempio Vesgum , oppure s?lice colloidale, per esem pio Aerosil . Come sostanze organiche macromolecola ri vengono adoperate per esempio, macromolecole naturali, semisintetiche e sintetiche. Pol?meri naturali e semi sintetici derivano per esempio da polisaccaridi con i pi? diversi costituenti di carboidrati, come cellulose, amidi, adragante, gomma arabica, agar-agar , gelatina, acido alginiee e suoi sali, per esempio alginato di sodio, e loro derivati come ?nf.alchilcellulose, per esempio metil- oppure etil-eelluloae, earbossi- impure idrossi-inf.alchilcellulose, per esempio carbossimetil- oppure idrossietil-cellulosa . I costituenti di macromolecole sintetiche, formanti gel, sono per esempio composti allietici insaturi corrispondentemente sostituiti, come alcool vinilico, vin?lpirrolidina, acido acr?lico oppure metaerilico. Cotao esempi di tali polimeri siano da nominare derida ti di alcool pol?v?niliso cose Polyv?ol, polivinile pirrolidine corno Kolli?cn, poliacrilati o rispetti? vamenfce polimetacrilati come Kohagit 5 oppure Eudispert. Ai geli possono venire aggiunti usuali additivi come sostanze conservanti od odor?se. anhydrous or poor in water, which are made up of swellable materials, formed gels. In the first place, transparent hydrogels based on inorganic or organic macromolecules are used. Macromolecular inorganic comonents with their own t? of goal formation are mainly aqueous silicets such as aluminum silicates, for example bentonite, magnesium-aluminum silicates - for example Vesgum, or colloidal silicates, for example Aerosil. For example, natural, semisynthetic and synthetic macromolecules are used as organic macromolecules. Natural and semi-synthetic polymers derive for example from polysaccharides with the pi? different constituents of carbohydrates, such as cellulose, starches, tragacanth, gum arabic, agar-agar, gelatin, alginiee acid and its salts, for example sodium alginate, and their derivatives such as? nf.alkylcellulose, for example methyl- or ethyl-eelluloae , impure earboxy hydroxy-lower alkylcellulose, for example carboxymethyl- or hydroxyethylcellulose. The constituents of synthetic, gel-forming macromolecules are, for example, correspondingly substituted unsaturated allyetic compounds, such as vinyl alcohol, vinyl pyrrolidine, acrylic or meta-ethyl acid. Cotao examples of such polymers are to be named derides of alcohol pol? V? Niliso things Polyv? Ol, polyvinyl pyrrolidine horn Kolli? Cn, polyacrylates or respects? vamenfce polymethacrylates such as Kohagit 5 or Eudispert. Usual additives such as preservatives or odors can be added to the gels.

Paste sono creme e pomate con costitu?nti polve ralenti assorbenti secrezioni, come ossidi metallici, per esempio ossido di titanio oppure ossido di zinco, inoltre talco e, oppure silicati di alluminio, i quali hanno il compito di legare umidit? presente o secrezioni. Pastes are creams and ointments with powdery constituents absorbing secretions, such as metal oxides, for example titanium oxide or zinc oxide, furthermore talc and / or aluminum silicates, which have the task of binding humidity. present or secretions.

Schiuso vengono erogate per esemplo da contenitori sotto pressione e sono emulsioni fluide olio in acqua, presenti sotto forma di aerosol, nel qual caso come propellenti vengono' impiegati idre carburi alogenati come clorofluoro-inf.alcani,. per esempio diclorodifluoro-metano e d?elorotetrafluoroetano. Come fase oleosa s? impiegano fra l'al tro idrocarburi, per esempio olio d? paraffina, al coll grassi per esempio alcool cetilico, estari di acidi grassi per esempio isoprepil-miristato e, oppure altre cere. Come emulsionatori si adoperano fra l' altre miscele d? quelli Con propriet? prevalentemente idrofilo, come esteri di acidi grassi di peliossietilensorbitano (Tweens) e quelli con propriet? prevalentemente lipofile, come esteri di acidi grassi di sorbitane (Spana). Vi si aggiungono gli usuali additivi cose conservanti ecc. Hatch are dispensed for example from containers under pressure and are fluid emulsions oil in water, present in the form of aerosols, in which case halogenated hydrocarbons such as chlorofluoro-lower alkanes are used as propellants. for example dichlorodifluoro-methane and d? elorotetrafluoroethane. How oily phase s? use among other hydrocarbons, for example oil d? paraffin, fatty acids, for example cetyl alcohol, esters of fatty acids, for example, isoprepil-myristate and / or other waxes. How emulsifiers are used among other mixtures d? those with propriet? predominantly hydrophilic, such as esters of fatty acids of hairyethylene sorbitan (Tweens) and those with properties? predominantly lipophilic, such as esters of fatty acids of sorbitane (Spana). The usual additives, preservatives, etc. are added.

Tinture e soluzioni presentano per lo pi? un fondamento etanolico a cui viene aggiunta eventilai mente acqua ed al quale s? aggiungono fra l' altro polialcoli, per esempio glicerina, glicoli e, oppuu re polietilenglicole a guisa d?. agenti di trattenuta di umidit? per diminuire la evapora z iene, e aostgn za reingrassanti, come esteri di acidi grassi con poliet?lenglicoli inferiori, cio? sostanze lipofile, solubili nella miscela acquosa, come sostitutivo per le sostanze grasse asportate dalla pelle con 1, etanolo e, se necessario, altri ausiliari ed ad dltivi. Dyes and solutions present mostly? an ethanolic foundation to which water is eventually added and to which s? they add, inter alia, sugar alcohols, for example glycerin, glycols and, or polyethylene glycol in the form of d ?. moisture retention agents to decrease evaporation, and re-greasing substances, such as esters of fatty acids with lower polyethylene glycols, that is? lipophilic substances, soluble in the aqueous mixture, as a substitute for fatty substances removed from the skin with 1, ethanol and, if necessary, other auxiliaries and additives.

La produzione dei preparati farmaceutici adope rabili in modo topico ha luogo in maniera di per se nota? per esempio mediante scioglimento o Sospensione della sostanza attiva nel sostrato od in una parto di esso, se necessario. Nella sommidetrazione della sostanza attiva sotto forma di soluzione, essa viene sciolta di regola ;in una delle due fasi prima dell s emulsionamentoi nella somministrazione sotto forma di sospensi?ne essa viene mescolata con una parte del sostrato, dopo lo emulsioaamento, e poi aggiunta al rimanente della formulazione? Does the production of topically usable pharmaceutical preparations take place in a per se known manner? for example by dissolving or suspending the active substance in the substrate or in a part thereof, if necessary. In the addition of the active substance in the form of a solution, it is dissolved as a rule; in one of the two phases before emulsification, in the administration in the form of suspensions, it is mixed with a part of the substrate, after emulsification, and then added to the remainder of the wording?

L?intenzione comprende parimenti 1 9 impiego dei nuoti rompesti della formula 1 a guisa di aniiinfiammato ri e, oppiare analgesici adoperabili per via pereutanea, preferibilmente sotto forma di corrisponde ti preparati farmaceutici. The intention also includes the use of the breakers of formula 1 as an inflammatory agent and opiates pereutaneously usable analgesics, preferably in the form of corresponding pharmaceutical preparations.

Gli esempi che seguono illustrano l ' invenzione sopra descritta. Essi tuttavia non debbono limitar la in alcun modo nel suo ambito. The following examples illustrate the invention described above. However, they must not limit it in any way in its scope.

Le temperature vengono indicate in ?C. Temperatures are indicated in? C.

Esempio 1 Example 1

Ad una soluzione di 2 g di acido 2- (2,6-41-. cioroanilino)-fenilacetico in 40 mi di etere si aggiungono 2 ml di dietilassaina . Lo soluzione vie ne riscaldata a riflusso per 10 minuti, viene raf freddata e concentrata a pressione ridotta, col To a solution of 2 g of 2- (2,6-41-. Cyoroanilino) -phenylacetic acid in 40 ml of ether, 2 ml of diethylassin are added. The solution is heated under reflux for 10 minutes, cooled and concentrated under reduced pressure, col

che si separa per cristallizzazione il 2- (2,6-dicloroanllino)-fenilacetato di dietilaia?dnlo? I cristalli incolori vengono separati per filtrazione (punte di fusione 110-115? decomposi zio that the 2- (2,6-dichloroanllino) -phenylacetate of diethylacetate separates by crystallization? dnlo? The colorless crystals are separated by filtration (melting points 110-115? Decomposition

ne) ed essiccati a temperatura ambiente sotto ne) and dried at room temperature below

alto vuoto. high vacuum.

In maniera analoga si ottengono, partendo da dietilammina e da acido 2-(6-metossi-2~naftil)propioni co il [2-(6-metossi-2-naftil)]-propionato di dietilammonio, punto di fusione 72-83? (decomposizione) e, partendo da dietilammina e da acido [l-(p-clorobenzoil )-5-metossi-2~metil-3-indolil] -acetico, il [l-(p-clorobenzoil)-5-metossi-2-metil-3-indolil]-acetato di dietilammonio, punto di fusione 98-125? (decomposizione) . In a similar way, starting from diethylamine and from 2- (6-methoxy-2-naphthyl) propionic acid, the [2- (6-methoxy-2-naphthyl)] - propionate of diethylammonium, melting point 72-83 ? (decomposition) and, starting from diethylamine and [1- (p-chlorobenzoyl) -5-methoxy-2 ~ methyl-3-indolyl] -acetic acid, [1- (p-chlorobenzoyl) -5-methoxy-2 -methyl-3-indolyl] -ethylammonium acetate, melting point 98-125? (decomposition).

Esempio 2 Example 2

Ad una soluzione di 10 g di acido 2-(2,6-dicloroanilino)-fenilacetico in 230 ml di estere eti lico di acido acetico si aggiungono a gocce a temperatura ambiente e con forte agitamento entro 10 minu ti 4,53 g di tris-(idrossimetil)-metilammina sciolti in 10 ml di acqua. Con ci? precipita immediata mente un sale. Successivamente si agita ancora per mezz?ora a temperatura ambiente e si allontana il solvente sul Rotavap. Il residuo bianco cristal lino viene sciolto in 1 litro di acetone/acqua (1:1) a circa 50?. La soluzione calda viene concentrata sul Rotavap finch? precipitano i primi cristalli. Poi si lascia cristallizzare a 0?. I cristalli bian chi fioccosi precipitati vengono filtrati por aspirazione ed essiccati sotto alto vuoto. Il 2-(2?6-dicloroanilina)-fenilacetato di tris- ( idrossimetti ) -metilamsonio cos? pttennte ha un posato d? fusione di 202-204?. To a solution of 10 g of 2- (2,6-dichloroanilino) -phenylacetic acid in 230 ml of ethyl ester of acetic acid, 4.53 g of tris are added dropwise at room temperature with strong stirring within 10 minutes. - (hydroxymethyl) -methylamine dissolved in 10 ml of water. With us? a salt immediately precipitates. The mixture is then stirred for another half hour at room temperature and the solvent is removed on the Rotavap. The white crystal flax residue is dissolved in 1 liter of acetone / water (1: 1) at about 50 ?. The hot solution is concentrated on the Rotavap until? the first crystals precipitate. Then it is allowed to crystallize at 0 ?. The precipitated white flaky crystals are filtered by suction and dried under high vacuum. The 2- (2? 6-dichloroaniline) -phenylacetate of tris- (hydroxymect) -methylamsonium so? pttennte has a posed d? merger of 202-204 ?.

Esempio 3 Example 3

Ad una soluzione di 10 g di acido 2- (2 .6-dicloroanilino)-fenilacetico in 230 ml di estere etilico di acido acetico si aggiungono a gocce a temperata ra ambiente e con forte agitamento entro 10 minuti 5,52 g di trietanolamina scipiti in 50 ml di estere etilico di acide acetico . In tal caso precipita immediatamente un sale. Successivamente si agita ancora per mezz?ora a temperatura ambiente ed il solvente viene allontanato sul Rotavap. Il residuo cristallino bianco viene sciolto in poco etanolo caldo e cristallizzato a 0?. I cristalli bianchi vengono filtrati per aspirazione ed essiccati s?t to alto vuoto. Il 2- (2 , 6-dicIaroanilino)-f eni!-acetato di trietanolammonio fonde a 137-138? To a solution of 10 g of 2- (2 .6-dichloroanilino) -phenylacetic acid in 230 ml of ethyl ester of acetic acid, add in drops at room temperature and with strong stirring within 10 minutes 5.52 g of triethanolamine. in 50 ml of ethyl ester of acetic acid. In this case, a salt immediately precipitates. The mixture is then stirred for another half hour at room temperature and the solvent is removed on the Rotavap. The white crystalline residue is dissolved in a little hot ethanol and crystallized at 0 ?. The white crystals are filtered by suction and dried under high vacuum. Triethanolammonium 2- (2, 6-dicyaroanilino) -fene! -Acetate melts at 137-138?

Esempio 4 Example 4

Ad una soluzione di 10 g di ?cido 2-(2,6~d?cloroanilino)-fenilacetico in 230 ml di estere etili co di acido acetico si aggiungono a gocce a temperatura ambiente e cosa forte agitamento entro 10 minati 3,89 g d? d?etanolama?na sospesi in 50 ml di estere etilico di acide acetico. In tal caso il sale formato precipita immediatamente. Successivament -te si agita ancora per mezz'ora a temperatura ambien te ed il solvente viene allontanato sul Botavap. To a solution of 10 g of? Cido 2- (2,6 ~ d? Chloroanilino) -phenylacetic acid in 230 ml of ethyl ester of acetic acid are added dropwise at room temperature and strong stirring within 10 minutes 3.89 g of ? d? ethanolama? na suspended in 50 ml of ethyl ester of acetic acid. In this case the formed salt precipitates immediately. Subsequently, the mixture is stirred for another half hour at room temperature and the solvent is removed on the Botavap.

Il residuo cristallino giallastro viene sciolto in poco etanolo bollente. La soluzione viene lasciata ia riposo a 0? per cui si separa per cristallizza zione il 2- (2 ,6-dicloroanil?no)-fenilacetato di dietanolamaonio, il quale presente un punto di fu sione di 150-132? . The yellowish crystalline residue is dissolved in a little boiling ethanol. Is the solution left to stand at 0? whereby the 2- (2, 6-dichloroanil? no) -phenylacetate of diethanolamonium is separated by crystallization, which has a melting point of 150-132? .

Ad una soluzione di 10 g di acido 2- (2 , 6-dielorosnilino)-fenilacetlco in 230 ml di estere et?lico di acido acetico vengono aggiunti a gocce a temperatura ambiente e con forte agitamento entro 10 minuti 3,22 g di morfolina in 30 al d? estere eti lice di acido acetico. Circa 10 minuti dopo l? aggioga ta di morf oline precipita un sale. Poi si sgita anco ra per 1 ora a temperatura ambiente ed il solvente viene allontanato sul Botavap. Successivamente il residuo cristallino bianco viene sciolte in etanolo boll ente. A 0? si separa per eri stalli stazione il 2- (2 , 6~dieloroanilino)-fenilacetato di morfolinio, il quale fonde a 162-165?. 3.22 g of morpholine are added dropwise at room temperature with strong stirring within 10 minutes to a solution of 10 g of 2- (2, 6-dielorosnilino) -phenylacetlc acid in 230 ml of ethyl ester of acetic acid. in 30 to the d? ethyl ester of acetic acid. About 10 minutes after l? a yoke of morph oline precipitates a salt. Then it is extracted again for 1 hour at room temperature and the solvent is removed on the Botavap. Subsequently the white crystalline residue is dissolved in boiling ethanol. At 0? the 2- (2, 6 ~ dieloroanilino) -phenylacetate of morpholinium separates for the first time, which melts at 162-165 ?.

In maniera analoga si ottengono, a partir da morfolina e da acido 2-(6-metossi-2-naftil)-propionico e rispettivamente da acido il- (p-clorobenzoil )-5-metossi-2-metil-3-indolil]- acetico, il [2- (6-metossi-2--naftil )]-propionato di morfolinio ed il In a similar way, starting from morpholine and 2- (6-methoxy-2-naphthyl) -propionic acid and respectively from il- (p-chlorobenzoyl) -5-methoxy-2-methyl-3-indolyl acid are obtained] - acetic, [2- (6-methoxy-2 - naphthyl)] - morpholinium propionate and

[1-(p-clorobensoil)-5-metossi-2-metil- - indolil]-acetato di sorf odialo. [1- (p-chlorobensoyl) -5-methoxy-2-methyl- - indolyl] -acetate of sorphidium.

Esempio 3 Example 3

Ad una soluzione di 10 g di acido 2- 2,6~dicloroanilino)-fenilacet?co in 230 ml di estere etilico di acido acetico si aggiungono a gocce a temperatura ambiente e con forte agitamento entro To a solution of 10 g of 2-2,6 ~ dichloroanilino) -phenylacetacic acid in 230 ml of ethyl ester of acetic acid are added dropwise at room temperature and with strong stirring within

5 minuti, 4, 92 g di diisopropilammina in 30 ml di estere etilico di acido acetico. Dopo breve tempo precipita un sale. Si agita ancora per 1 ora, si allontana il solvente sul Rotavap e si scioglie 5 minutes, 4.82 g diisopropylamine in 30 ml of ethyl ester of acetic acid. After a short time a salt precipitates. The mixture is stirred for another hour, the solvent is removed on the Rotavap and dissolved

il res?duo cristallino bianco in poco etanolo bollente? le soluzione viene lasciata in ripeso a 0% col che si separa per cristallizzazione il 2-(2,6-dicloroanilino)-fenilacetato di diisopropanolammonio con un punto di fissione di 185-170? . the white crystalline res? duo in a little boiling ethanol? The solution is left in the 0% weight with which the 2- (2,6-dichloroanilino) -phenylacetate of diisopropanolammonium is separated by crystallization with a fission point of 185-170? .

Esempio 7 Example 7

Una sospensione di 6? 64 g di N-metil-D-glucammina in 100 ml, di etanolo insieme con 10 g di acido 2~(2,6~dieloroaniXino)-fenilacetico in 230 ml di estere etilico d? acido acetico viene agitata a temperatura ambiente per una notte sotto azoto. A suspension of 6? 64 g of N-methyl-D-glucamine in 100 ml, of ethanol together with 10 g of 2 ~ (2,6 ~ dieloroaniXino) -phenylacetic acid in 230 ml of ethyl ester d? acetic acid is stirred at room temperature overnight under nitrogen.

Dopo 2 ore precipitano cristalli fini, bianchi. Poi il solvente viene allontanato sul Rotavap ed il residno appiccicoso bianco viene sciolto in poca acqua calda. Successivamente la soluzione limpida viene lasciata raffreddare lentamente a 0? e lasciata in riposo per una notte a 0?. Precipita una massa oleo sa, semicristallina, che viene separata per filtra zig, ne per due giorni attraverso un filtro di (Jelite e di stoffa. Il materiale sul filtro viene essiccato per ima settimana a 60?/100 mm di Mg e successivamente ridotto in polvere. Il 2-(2,e-dicloroaail?no)-fen?lacetato di N-met?l-D-glueammonio fonde a After 2 hours, fine, white crystals precipitate. Then the solvent is removed on the Rotavap and the white sticky residue is dissolved in a little hot water. The clear solution is then allowed to slowly cool to 0 ° C. and left to rest overnight at 0 ?. An oily, semi-crystalline mass precipitates, which is separated by zig filtering for two days through a Jelite and cloth filter. The material on the filter is dried for a week at 60? / 100 mm of Mg and subsequently reduced in powder. 2- (2, e-dichloroaail? no) -phen? N-meth? l-D-glueamonium lacetate melts to

127-130?. 127-130 ?.

Esempio 8 Example 8

Una pomata, contenente 5% di 2-(2,6-dicloroanilino)fenilacetato di dietilammonio viene preparata come segue; An ointment, containing 5% diethylammonium 2- (2,6-dichloroanilino) phenylacetate is prepared as follows;

La sostanza attiva viene sciolta in una misge la di glicerina e di propilenglicole e gli altri componenti vengono fusi, insieme. Successivamente la soluzione di sostanza attiva viene introdotta per emulsionamento nella fase grassa? Dopo agitamento a freddo, se si desidera, si aggiunge sostan za odorosa (0,1%)? The active substance is dissolved in a mixture of glycerin and propylene glycol and the other components are fused together. Is the solution of active substance subsequently introduced by emulsification in the fat phase? After cold stirring, if desired, an odorous substance (0.1%) is added?

In maniera analoga si ottiene una pomata cont nente 0,5% oppure 2% di sostanza attiva? Esempio 9 In the same way, is an ointment containing 0.5% or 2% of active substance obtained? Example 9

Un idrogel trasparente, contenente 5% di 2~ (2 , 6-cicloroanilino)-fenilacetato d? diotilammonio, viene preparato come segue: A clear hydrogel, containing 5% 2 ~ (2, 6-cycloroanilino) -phenylacetate d? diotylammonium, is prepared as follows:

La idrossipropilset?l-cellulosa viene rigonfiata in acqua. La sostanza attiva viene sciolta in una miscela di isopropanolo e di propilenglico le. Successivamente la soluzione di sostanza atti va viene mescolata con il derivato di cellulosa rigonfiato e, se lo si desidera, si aggiungono so stanze odorose (0,1%). The hydroxypropylset? L-cellulose is swollen in water. The active substance is dissolved in a mixture of isopropanol and propylene glycol. Subsequently, the solution of active substance is mixed with the swollen cellulose derivative and, if desired, odorous substances (0.1%) are added.

In maniera analoga si ottiene un gel contenente 0,5% oppure 2% della sostanza attiva. In a similar way, a gel containing 0.5% or 2% of the active substance is obtained.

Esempio 10 Example 10

Un idrogel trasparente, contenente 5% di 2-(2,6~dicloroanilino)-fen?lacetato di dietilaramo nio, viene preparato come segue: A clear hydrogel, containing 5% 2- (2,6 ~ dichloroanilino) -phen? Diethyl aramylacetate, is prepared as follows:

Polimero di acido acrilico ed acqua vengono dispersi e neutralizzati con trietanolammina. La sostanza attiva viene sciolta in una miscela di iso propendo e di propileng??co?e? Successivamente la soluzione di sostanza attiva viene mescolata con il gel mentre, se si desidera, pu? venire aggiunta sostanza odorosa (0,1%). Polymer of acrylic acid and water are dispersed and neutralized with triethanolamine. The active substance is dissolved in a mixture of iso propend and propylene ?? co? E? Subsequently the solution of active substance is mixed with the gel while, if desired, can? odorous substance (0.1%) is added.

In maniera analoga si ottengono geli contenenti 0,5% oppure 2% della sostanza attiva? In a similar way, are gels containing 0.5% or 2% of the active substance obtained?

Esempio 11 Example 11

Una microemulsione trasparente, contenente 5% di 2-(2?6~dicloroanilino}-fenilacetato di dietilammonio? viene preparata come segue: A clear microemulsion, containing 5% diethylammonium 2- (2? 6 ~ dichloroanilino} -phenylacetate? Is prepared as follows:

Alcool ceti?stearilieo ed estere poliolico di acido grasso vengono riscaldati a 95? ed in essi si scioglie la sostanza attiva. Vi si aggiunge una miscela, riscaldata a 95? , di acqua e di glicerina e, se desiderato, di conservante (0,2%). La microemulsione risultante viene raffreddata .agitan do ed eventualmente addizionata di sostanza odorosa (0,1$)? Ceti? Stearyl alcohol and fatty acid polyol ester are heated to 95? and the active substance dissolves in them. A mixture is added to it, heated to 95? , water and glycerin and, if desired, a preservative (0.2%). The resulting microemulsion is cooled with agitation and optionally added with an odorous substance (0.1%)?

In maniera analoga si ottengono microemulsioni trasparenti , contenenti 0 ,5% oppure 2% della sostan za attiva. In a similar way, transparent microemulsions are obtained, containing 0, 5% or 2% of the active substance.

Esempio 12 Example 12

Una lozione? contenente 5% di 2~(2,6-dicloroanilino )-fenilacetato di dietilammonio, viene pre parata c?me segue: A lotion? containing 5% diethylammonium 2 ~ (2,6-dichloroanilino) -phenylacetate, it is prepared as follows:

La sostanza attiva ed i parabeni vengono sciol ti in acqua e propilenglicole. Poi alla soluzione di sostanza attiva si aggiunge etere pol?ossi?tilencetil stearilico. Estere decilico di acido oleico ed i gliceridi degli acidi grassi con stearato d? potassio vengono fusi insieme ed introdotti per emulsionamento nella fase acquosa. La lozione vie ne agitata a. freddo ed eventualmente addizionata di sostanze odorose (0,1%). The active substance and the parabens are dissolved in water and propylene glycol. Then pol? Oxy? Tylene methyl stearyl ether is added to the solution of active substance. Decyl ester of oleic acid and the glycerides of fatty acids with stearate d? potassium are fused together and introduced by emulsification into the aqueous phase. The lotion is stirred a. cold and possibly added with odorous substances (0.1%).

Una soluzione, contenente 5% di 2-(2,6-diclorcaniline )-fenilacetato di dietilammonio, viene preparata come segue: A solution, containing 5% diethylammonium 2- (2,6-dichlorkaniline) -phenylacetate, is prepared as follows:

La sostanza attiva viene sciolta in etanolo e l'estere di acido grasso di poliossietilensorbitaao viene sciolto in trigliceride liquido. Le due soluzioni vengono mescolate. Se lo si desidera, vengono aggiunte addizionalmente sostanze odorose (0,1%)? The active substance is dissolved in ethanol and the polyoxyethylene sorbed fatty acid ester dissolved in liquid triglyceride. The two solutions are mixed. If desired, are odorous substances added (0.1%) additionally?

In maniera analoga si ottengono soluzioni con tenenti 0,5# o rispettivamente 2%. della sostanza attiva. In a similar manner, solutions containing 0.5% or 2% respectively are obtained. of the active substance.

Esempio 14 Example 14

Una pomata, contenente 5 % di 2-(2,6-d?cloroan?lino)-fenilacetato di dietilammonio, viene pre parata come segue: An ointment, containing 5% diethylammonium 2- (2,6-d? Chloroan? Linen) -phenylacetate, is prepared as follows:

La sostanza attiva viene sciolta in propilenglicoie ed acqua. Mono- e digliceridi di acidi gras si saturi superiori con stearato di potassio vengono fusi insieme con estere decilico di acido oleico. The active substance is dissolved in propylene glycol and water. Mono- and diglycerides of higher saturated fatty acids with potassium stearate are fused together with decyl ester of oleic acid.

Successivamente la fase acquosa viene introdotta nel la fase grassa e si emulsiona e, se lo si desidera, si aggiungono sostanze odorose (0,1%). Subsequently, the aqueous phase is introduced into the fat phase and emulsified and, if desired, odorous substances (0.1%) are added.

In maniera; analoga si ottiene una pomata conte n?nte 0,5% o 2% della sostanza attiva. In a manner; a similar ointment is obtained containing 0.5% or 2% of the active substance.

Esempio, 15 Example, 15

Una pomata, contenente 5% di 2- (2 ,6-dicloroanilino)^fenilacetato di dietilammonio, viene pre parata nel modo seguente; An ointment, containing 5% diethylammonium 2- (2, 6-dichloroanilino) ^ phenylacetate, is prepared as follows;

La sostanza attive viene sciolta in propilenglicole ed acqua. I costituenti grassi vaselina, cera, non che estere di acido grasso di sorbitano vengono fusi insieme . Successivamente la soluzione di sostanza attiva viene immessa per emulsionamento nella fase grassa e, se desiderato, si aggiungono sostai ze odorose (0,1%) , The active substance is dissolved in propylene glycol and water. The fatty constituents petroleum jelly, wax, not that sorbitan fatty acid ester are fused together. Subsequently, the solution of active substance is introduced by emulsification into the fat phase and, if desired, odorous residues (0.1%) are added,

In maniera analoga si ottiene una pomata conte nenie 0,5% o 2% della sostanza attiva, In a similar way, an ointment containing 0.5% or 2% of the active substance is obtained,

Una lozione, contenente 2% di 2- (2 , 6-dicloroanilino)-fenilacetato di dietilammonio, viene prepa rata come segue: A lotion, containing 2% diethylammonium 2- (2, 6-dichloroanilino) -phenylacetate, is prepared as follows:

La sostanza attiva viene sciolta in pol?alchilenglicole ed acqua, Triglicer?de, olio di paraffina ed estere di acido grasso di glieer?na-sorbitano vengono fusi insieme. Successivamente ila fase acquosa viene emulsionata nella fase grassa. Se si desidera, vengono aggiunte sostanze odorose (0,1%), The active substance is dissolved in polyalkylene glycol and water, Triglycerin, paraffin oil and glycerol na-sorbitan fatty acid ester are fused together. Subsequently the aqueous phase is emulsified in the fat phase. If desired, odorous substances are added (0.1%),

Claims

1. Topically applicable pharmaceutical preparations containing compounds of the formula

(THE)

where R1 represents a group of the formula

(Ia)

in which X1 and X2 indicate hydrogen and X3 indicates isobutyl, or X1 and X2 represent hydrogen and X2 represents benzoyl, or X1 indicates hydrogen, X2 indicates chlorine and X3 indicates 3-pyrrolin-1-yl, or X1 represents hydrogen, represents a group of the formula

together with X4 represents a bond, and R2 each time indicates methyl, or X2 and X3 represent

hydrogen and X1 represents 2,6-dichloro-aniline, ed

R2 indicates hydrogen, or R1 indicates a group of

the formula

(Ib)

in which X5 represents the common link eoa

the methine group of the formula I, X6 and X7 indicates

no hydrogen, X8 represents p-methylbenzo? le, Y? a

atom of nitrogen and X9 indicates a methyl group, or X5? a methyl group, X6 represents a common bond with the methyl group in the formula

I, Xp denotes a group of the formula

X8 together with X10 represents a bond, I? an ato.

mo d? nitrogen, and indicates p-chlorobenzoyl, or X5

? a methyl group, X6 represents the bond in coma with the methyl group in the formula X, X7 indicates

a group of the formula X8 together

me with X11 indicates a link, I? an atom of G, and represents (p-iaethansolfinylphenyl) -methylene, and

R2 indicates hydrogen each time, and R3 and and R5 independently of each other represent hydra

genus, an aliphatic radical, or two of the radicals R4 and R5 together represent a bivalent aliphatic radical, unsubstituted or substituted or interrupted by aza, bones or thia, with the condition that at least one of the radicals R3, R4 and R5 is different from hydrogen, possibly in the form of an isomer, alongside the auxiliaries and / or additives usual for topical application.

2. Topically applicable pharmaceutical preparations according to claim 1, containing a compound of formula I, in which R1 and R2 have the meanings indicated at the beginning, R3, R4 and R5 independently from each other represent hydrogen, a unsubstituted lower alkyl radical or amino substituted by a group of the formula

or by means of hydroxyl, or? two of the radicals R3, R4 and R5 indicate lower alkylene with 4 to 7 members or lower alkylene with 4 to 7 members interrupted by azay possibly containing lower alkyl, or through bones or thia, with the condition that at least one of the radicals R3, R4 and R5 is different from hydrogen, alongside the usual auxiliaries and additives for topical application?

3. Topically applicable pharmaceutical preparations according to claim 1, containing a compound of formula I, in which R1 and R2 have the meanings indicated at the beginning, and R3, R4 and R5 independently of each other indicate inf. alkyl with up to 4 including atoms of C, as motile or ethyl, or hydroxy-lower alkyl with up to 4 including atoms of C or red-lower alkyl

with up to 4 including atoms of C, or one of the radicals R3, R4 and R5 indicates hydrogen and the others, independently of each other, indicate lower-alkyl with up to 4 including atoms of C, hydroxy-alkyl with up to 4 including atoms d? C, or together with lower alkylene with 4 to 7 members? aza possibly N-lower alkylate or oxa- or t? a-lower alkylene with 4 to 7 members, or one of the others indicates lower alkyl with up to 4 included atoms of C and the third indicates oligo-hydroxy-lower alkyl , or two from the radicals R3, R4 and R5 represent hydrogen and the other represents lower-alohyl with up to 4 including atoms of C, hydroxy-lower alkyl with up to 4 inclusive, atoms of C, oligohydroxy-lower. alkyl with up to 4 including atoms of C, amino-lower alkyl with up to 4 including atoses of C or a group of the formula

in which alk indicates lower alkylene with up to 4 including atoms of C, alongside the usual auxiliaries and additives for topical application.

4. Topically applicable pharmaceutical preparations according to claim 1, containing a compound of the formula I, wherein R1 indicates a group of the formula IIa in which X1 represents hydrogen, X2 represents a group of the formula

and X2 together with X4 represents?

feel a bond, and R2? methyl, or in which? ndica a group of the formula He, in which X1? 2,6-dichloroanilino, X2 and represent hydrogen, and R2? hydrogen, or in which it indicates a group of formula IIb in which X5? a methyl group, X6 represents the bond in common with the methyl group of the formula (X), X7 indicates a group of the formula

X8 together with X10 rap ~

presents a link, I? a nitrogen atom and denotes p-chlorobenzoyl, and? ? hydrogen, and R3, and R5 have the immediately preceding meanings, alongside the usual auxiliaries and additives for topical application.

5. Pharmaceutical preparations applicable in topical aode according to claim 1, containing a compound deliafOrmala I? in which and Bg have the immediately preceding meanings, and and as well as? indicate hydroxy-lower alkyl with up to 4 including C atoms, or one of the radicals R3, R4 and R5 indicates hydrogen and the others indicate lower alkyl with up to 4 including C atoms, hydroxyl lower alkyl with up to 4 including C or ssainf atoms. 4 to 7 membered alkylene, alongside the usual auxiliaries and additives for topical application.

6. Topically applicable pharmaceutical preparations according to claim 1, containing a compound of the formula -I? in which: R1 indicates a group of the formula IIa in which it represents

2,6-dichloroanilino, and X2 and X3 represent hydrogen, and R2? hydrogen? and R3, R4 and R5 have the meaning indicated above, alongside the same auxiliaries and additives for topical application.

7. Topically applicable pharmaceutical preparations according to claim 1, containing a compound of formula I, in which R1 and R2 have the meanings named immediately above, and one of the radicals R3, R4 and R5 indicates hydrogen and the others represent? nf. alkyl with up to 4 included atoms of C or 3-bone-lower alkylene with 4 to 7 members, alongside the usual auxiliaries and additives

for topical application.

8. Topically applicable pharmaceutical preparations according to claim 1, containing

2? (2,6-dichloroanilino) -phenylacetate diethylammonium, alongside the usual auxiliaries and additives

them for topical application.

9. Topically applicable pharmaceutical preparations according to claim 1, containing

[2- (6-methoxy-2-naphthyl) 3-propionate of diethylammonium, alongside the usual auxiliaries and additives for topical application,

10. Topically applicable pharmaceutical preparations according to claim 1, containing

[1- (p-chlorobenzoyl) -5 * methoxy-2-methyl ~ 5-1tpdolyl3-diethylammonium acetate, adjuvant

and usual additives for topical application.

11. Topically applicable pharmaceutical preparations according to claim 1, containing 2?

(2, 6-dichloroanil? No) -tris- (hydroxy? Methyl) -methylammonium phenylacetate, alongside the auxiliary and usual additives for topical application.

12. Topically applicable pharmaceutical preparations according to claim 1, containing 2- (2, 6 ~ dichloroanilino) -phenylacetate d? fcriethanolammonium, alongside the usual auxiliaries and additives for topical application.

13. Topically applicable pharmaceutical preparations according to claim 1, containing diethanolammonium 2- (2,6-dichloroanilino) -phenylheetate, alongside the usual auxiliaries and additives for topical application?

14. Topically applicable pharmaceutical preparations according to claim 1, containing morphclinium 2- (2,6-dichloroanil? No) -phen? Lacetate, alongside the usual auxiliaries and additives for topical application?

15. Topically applicable pharmaceutical preparations according to claim 1, containing [2 ~ (6-methoxy-2 ~ naphthyl) 3? morpho linium propionate, alongside the usual auxiliaries and additives for topical application?

16. Topically applicable pharmaceutical preparations according to claim 1, containing

[1- (p-chlorobenzoyl) -5-methoxy-2-methyl-3-indolyl] -acetate? I morpholinium, alongside the usual auxiliaries and additives for topical application.

17 Topically applicable pharmaceutical preparations according to claim 1, containing diisopropane ammonium 2- (2,6-dichloroanilino) -phenylacetate, alongside the auxiliaries and additives usual for topical application.

18. Topically applicable pharmaceutical preparations according to claim 1, containing 2- (2,6-dichloroanilino) -phenylacetate of N-methyl-D-glucammonium, alongside the usual auxiliaries and additives for topical application.

19. Process for the production of topically applicable pharmaceutical preparations, characterized by what? than a compound of the formula

(THE)

where R1 represents a group of the formula

(Ila)

in the actual X1 and indicate hydrogen and X3 indicates isobutyl, or X1 and represent hydrogen and Xg represents benzoyl, or X1 indicates hydrogen, indicates chlorine and X3 indicates 3-pyrrolin-1-yl, or X1 represents hydrogen, X2 represents a group of the formula

together with X4 represents a bond, and indicates

each time methyl, or and X3 represent

hydrogen and X1 represents 2,6-dichloro-aniline, ed

R2 indicates hydrogen, or where R1 indicates a group of

the formula

(IIb)

in which it represents the link in common with

the methine group of the formula I, X6- and X7 indicates

no hydrogen, X8 represents p-methylbenzoyl, Y? a

atom of nitrogen and X9 indicates a methyl group, or in which X5? a methyl group, X6 represents a common bond with the methyl group of the formula

I, X7 indicates a group of the formula

? 8 together with X10 represents a bond, Y? an ato

mo of nitrogen, and X9 indicates p-chlorobenzoyl, or X5 in its name? a methyl group, X6 represents the bond in common with the methyl group of the formula I, X7 indicates

a group of the formula X8 together

me with indicates a tie, Y? an atom of C, ed

X9 represents (p-methanesolfinylphenyl) -methylene, ed

R2 denotes hydrogen each time, and in which R3, R4 and R5 independently of each other represent hydrogen, an aliphatic radical, or two of the radicals R3, R4 and R5 together represent a divalent, unsubstituted or substitute aliphatic radical. to or interrupted by aza, bones or thia, with the condition that at least one of the radicals R3, R4 and R5 is different from ... hydrogen, possibly in the form of an isomer, is mixed with auxiliaries and additives usual for topical application .

20. Compounds of formula I, in which R1 represents a group of formula IIa in which X1 indicates hydrogen, X2 represents A group of the formula and X3 together with X4 indicates a bond,? methyl, and R3, R4 as well as?

R5 represent ethyl or 2-hydroxy-ethyl, or one of the radicals R3, R4 and R5 represents hydrogen and the others represent ethyl, 2-hydroxyethyl or 3-oxo-1,5-pentylene, or wherein R1? a group of formula IIa in which X1 indicates 2,6-dichloroanilino and X ^ indicate hydrogen, R2? hydrogen and one of the radicals R3, R4 as well as? R5 represents hydrogen and the others represent ethyl, or indicate hydrogen, R4 methyl and R5 D-pentahydroxyethyl derived from 1-glucamine, or the radicals R3, R4 and R5 each time indicate 2-hydroxy-ethyl, or where

R1? a group of the formula Ilb in which X5

indicates methyl? represents a legai? in common and or in the methyl group of formula I? L? ? u? group of the formula together goose X10 indicates a bond, Y? a nitrogen atom and X9 represents p-chlorobensoyl, R2 indicates hydrogen, and R3, R4 as well as? R5 denote hydroxy-lower alkyl with up to 4 including G or ethyl atoms, or two of the radicals R3, R4 and represent hydroxy-lower alkyl with up to 4 including 0 or ethyl atoms, and the other? hydrogen, or one of the radicals R3, R4 and R5? hydroxy-lower alkyl with up to 4 inclusive atoms of C or ethyl, and the others denote hydrogen, or an isomer thereof.

21. Compounds of formula 1 according to claim 20, wherein R1 indicates a group of formula 11a in which X1 indicates hydrogen, X2 represents a group of the forauIa and

X3 together with indicates a bond, R2? methyl, and R3 R4 as well as? R5 represent ethyl or

2-hydroxy-ethyl, yet one of the radicals R3 R4 and R5 represents hydrogen and the others represent ethyl, 2-hydroxy-ethyl or 3-oxo-1,5-Pentylene.

22. Compounds of formula I according to rivren dieation 20 in which R1? a group of formula IIa in which X1 indicates 2,6-dioloroaniline, X2 and X3 indicate hydrogen, R? hydrogen, and one of the radicals R3 R4 as well as? R5 represents hydrogen and the others represent ethyl, or the radicals R3, R4 and R5 each indicate hydresalatile.

23. Compounds of formula I according to reaction reaction 20, wherein represents a group of formula llb in which X5 indicates methyl, X6 represents a common bond with the methysical group of formula I, Xy? m group of the formu the X8 together with X10 indicates a link, Y? an atom of nitrogen and represents p-chlorobenzoyl, B2 indicates hydrogen, and R3 R4 as well as? R5 denote hydroxy-lower-alkyl with up to 4 including C atoml or ethyl, or two of the 3? A dicals R3, R4 and R5 represent hydroxy-lower-alkyl with up to 4 including C atoml or ethyl, and 'other ? hydrogen, or one of the radios R3, R4 and R5? hydroxyl-lower alkyl with up to 4 inclusive C or ethyl atoms, and the others indicate hydrogen.

24. 2 ~ (2, 6-dieloroaGiXino) ~ diethylammon phenylacetate? Or?

25. [2- (6-methoxy-2-naphthyl)] - diethylansaonium propionate or one of its isomars.

26. [1- (p-chlorobenzoyl) -5-methoxy-methyl3-indolyl] -dictylammonium acetate.

27. 2- (2,6-dichloroanilino) -phenylacetate of triethanolammonium *

28. 2- (2, 6-dichloroanilino) -phenylacetate of diianclsimaoni or *

29. 2 -? (2,6-dichloroanilino) -phenylacetate of aorfol? Nio *

30. 2- (2,6-dichloroanilino) -phenylacetate of N-methyl-D-glucaminium.

31. Pharmaceutical preparations containing as the active substance a compound of formula I according to one of claims 20 to 30, alongside pharmaceutical auxiliaries and / or support materials.

32. Pharmaceutical preparations according to claim 31, for the topical applicalone,?

33. Pharmaceutical preparations dry any of claims 1 to .13 as well as? 31 and 32, containing about 0.5 to about 5% by weight of the active substance, alongside the usual pharmaceutical auxiliaries and support materials.

A compound according to any of claims 20 to 30 for use in a process for the therapeutic treatment of the human or animal body.

35. Compound according to any of claims 20 to 30 for use according to the claim anti-inflammatory and / or analgesic products.

36. Process for the production of compounds of formula I according to any of claims 20 to 30, characterized in that than an organic acicarboxyl of the formula

(IIIa)

or a different basic salt thereof, from a salt of the formula I is reacted with a quantity? at least equimolar of the amine of the formula

(IIIb)

or with an addition salt thereof with acid and, if desired, a compound of formula I obtainable according to the hygiene procedure transformed into one other compound of formula I and, or a mixture of isomers obtainable according to the procedure separated into its components.

37. Process according to claim 36, characterized in that that the starting substances are prepared on site or a substance d? starting point is obtained under the reaction conditions from a derivative and / or is used in the form of a mixture of isomers and in the form of a pure isomer and / or a salt.

38. Use of compounds of formula I according to any of claims 20 to 30, for the production of pharmaceutical preparations.

39. use according to claim 38, for the production of topically applicable pharmaceutical preparations.

40. Use of compounds of formula I according to any of claims 20 to 30 as an anti-inflammatory and / or analgesic.

41. The compounds described in Examples 1 to

or 7.

42. The procedure of examples 1 to 7,

43. The formulations described in examples 8 through 16.

44. The processes described in examples 8 to 16 for the production of topically applicable pharmaceutical preparations.

45. Process for the production of topically applicable pharmaceutical preparations, characterized by this that a compound of formula I according to any one of claims 20 to 30 is mixed with auxiliaries and support materials usual for topical application.

/ V /

IJ I <'> v? ?

eoo NH (e H-)

\ - 25?

\ ^ Y

? -. <? > there

'{<?>

In a similar way, starting from diethylamine and 2- (6-methoxy-2-naphthyl) propionic acid are obtained with [2- (6-methoxy-2-naphthyl)] - diethylammonium propionate, melting point 72 -83? (decomposition) and, starting from diethylamine and [1- (p-chlorobenzoyl) -5-methoxy-2-methyl-3-indolyl] -acetic acid, [1- (p-chlorobenzoyl) -5-methoxy-2 -methyl-3-indolyl] -ethylammonium acetate, melting point 98-125? (decbmposition).

Example 2

4-, 53 g of tris- (hydroxymethyl) -methylamine dissolved in 10 ml of water. With us? a salt immediately precipitates. Subsequently, the mixture is stirred for another half hour at room temperature and the solvent is removed on the Eotavap. The white crystal flax residue is dissolved in 1 liter of acetone / water (1: 1) at about 50 ?? The hot solution is concentrated