ITMI981743A1 - Sali nitratti di farmaci - Google Patents

Sali nitratti di farmaci Download PDF

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Publication number
ITMI981743A1
ITMI981743A1 IT98MI001743A ITMI981743A ITMI981743A1 IT MI981743 A1 ITMI981743 A1 IT MI981743A1 IT 98MI001743 A IT98MI001743 A IT 98MI001743A IT MI981743 A ITMI981743 A IT MI981743A IT MI981743 A1 ITMI981743 A1 IT MI981743A1
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IT
Italy
Prior art keywords
formula
nitrate
salts
salt
compounds
Prior art date
Application number
IT98MI001743A
Other languages
English (en)
Original Assignee
Nicox Sa
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Nicox Sa filed Critical Nicox Sa
Publication of ITMI981743A0 publication Critical patent/ITMI981743A0/it
Priority to IT1998MI001743A priority Critical patent/IT1303671B1/it
Priority to AU52857/99A priority patent/AU770313C/en
Priority to EP99938300A priority patent/EP1098870B1/en
Priority to CNB998090425A priority patent/CN1264828C/zh
Priority to DK99938300T priority patent/DK1098870T3/da
Priority to IL14068599A priority patent/IL140685A0/xx
Priority to ES99938300T priority patent/ES2252958T3/es
Priority to AT99938300T priority patent/ATE307796T1/de
Priority to JP2000562338A priority patent/JP4455760B2/ja
Priority to PCT/EP1999/005171 priority patent/WO2000006531A2/en
Priority to RU2001102262/04A priority patent/RU2254330C2/ru
Priority to BR9912375-4A priority patent/BR9912375A/pt
Priority to SI9930862T priority patent/SI1098870T1/sl
Priority to HU0102706A priority patent/HUP0102706A3/hu
Priority to US09/743,808 priority patent/US6410791B1/en
Priority to KR1020017000803A priority patent/KR100687806B1/ko
Priority to DE69927977T priority patent/DE69927977T2/de
Priority to CA2338854A priority patent/CA2338854C/en
Publication of ITMI981743A1 publication Critical patent/ITMI981743A1/it
Priority to ZA200100457A priority patent/ZA200100457B/en
Application granted granted Critical
Publication of IT1303671B1 publication Critical patent/IT1303671B1/it
Priority to US10/151,955 priority patent/US6828342B2/en
Priority to US10/736,688 priority patent/US7122539B2/en
Priority to AU2004201457A priority patent/AU2004201457A1/en

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    • G—PHYSICS
    • G06—COMPUTING; CALCULATING OR COUNTING
    • G06Q—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR ADMINISTRATIVE, COMMERCIAL, FINANCIAL, MANAGERIAL OR SUPERVISORY PURPOSES; SYSTEMS OR METHODS SPECIALLY ADAPTED FOR ADMINISTRATIVE, COMMERCIAL, FINANCIAL, MANAGERIAL OR SUPERVISORY PURPOSES, NOT OTHERWISE PROVIDED FOR
    • G06Q20/00—Payment architectures, schemes or protocols
    • G06Q20/04—Payment circuits
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/33—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C07C211/34—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of a saturated carbon skeleton
    • C07C211/35—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of a saturated carbon skeleton containing only non-condensed rings
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • C07C215/42—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having amino groups or hydroxy groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C215/44—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having amino groups or hydroxy groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton bound to carbon atoms of the same ring or condensed ring system
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    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • C07C215/46—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C215/56—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains further substituted by hydroxy groups
    • C07C215/58—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains further substituted by hydroxy groups with hydroxy groups and the six-membered aromatic ring, or the condensed ring system containing that ring, bound to the same carbon atom of the carbon chain
    • C07C215/60—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains further substituted by hydroxy groups with hydroxy groups and the six-membered aromatic ring, or the condensed ring system containing that ring, bound to the same carbon atom of the carbon chain the chain having two carbon atoms between the amino groups and the six-membered aromatic ring or the condensed ring system containing that ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
    • C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
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    • C07D—HETEROCYCLIC COMPOUNDS
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/86—Hydrazides; Thio or imino analogues thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/22—Bridged ring systems
    • C07D221/28—Morphinans
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/91—Nitro radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D241/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
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    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
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Description

Descrizione dell'invenzione industriale a nome:
La presente invenzione riguarda composti o loro composi zioni farmaceutiche, per uso sistemico e non, da utilizzarsi nel trattamento di patologie del sistema respiratorio, in particolare malattie croniche ostruttive polmonari (chronic obstructive pulmonary disease (COPD)), quali asma, bronchiti, enfisema, con minori effetti collaterali rispetto ai farmaci attualmente utilizzati per il trattamento di queste patologie.
E' noto nell'arte che per il trattamento di queste patologie i prodotti più utilizzati sono il Salbutamolo, Salmoterolo, ecc. Si veda ad esempio il volume "Textbook of Therapeutics - Drugs and Disease Management - 6th Edition 1996" pag. 685. Questi prodotti sono efficaci ma hanno lo svantaggio di dare effetti collaterali in particolare a carico dell'apparato cardiovascolare. Questo ne rende problematica spesso l'accettazione da parte del paziente affetti da patologie cardiovascolari.
Altri prodotti utilizzati in queste patologie tal quali o come coadiuvanti di altri farmaci sono ad esempio Ambroxol, e Bromexina la cui somministrazione é accompagnata anche dalla comparsa di effetti collaterali a carico dell'apparato gastrointestinale, quali ad esempio bruciori ed irritabilità gastrica .
Era sentita l'esigenza di avere a disposizione composti, e loro composizioni farmaceutiche, che fossero efficaci nel trattamento delle patologie del sistema respiratorio, combinati con minori effetti collaterali a carico dell'apparato cardiovascolare e/o dell'apparato gastrointestinale.
La Richiedente ha inaspettatamente e sorprendentemente trovato specifici composti e loro composizioni che risolvono il problema tecnico sopra indicato.
Costituisce un oggetto della presente invenzione sali nitrati di composti, o loro composizioni farmaceutiche, da utilizzarsi per il trattamento di patologie del sistema respiratorio, in particolare malattie croniche ostruttive polmonari <(>chronic obstructive pulmonary disease (COPD)), quali asma, bronchiti, enfisema, detti composti essendo caratterizzati dal fatto di contenere almeno un gruppo reattivo in grado di venire salificato con acido nitrico, detti composti scelti tra i seguenti :
Salbutamolo avente formula (I)
Cetrizina avente formula (II)
Loratidina avente formula (III<) >
Terfenadina avente formula (IV)
Emedastina avente formula (V)
Ketotifene avente formula (VI)
Nedocromil avente formula (Vili
Ambroxolo avente formula (Vili )
Bromexina avente formula (IX)
Destrometorf ano avente formula (X)
I composti preferiti sono Salbutamolo, noto anche come Albuterolo, Cetirizina, Emedastina, Ambroxolo.
I sali nitrati della presente invenzione possono venir ottenuti anche impiegando i composti sopra indicati, che opzionalmente contengano uno o più gruppi -ONO2 legati covalentemente alla molecola mediante uno dei seguenti ponti di collegamento bivalenti:
YO in cui Y è un alchilene C1-C20 lineare o ramificato quando possibile, preferibilmente da 2 a 5 atomi di carbonio, o un cicloalchilene da 5 a 7 atomi di carbonio eventualmente sostituito;
Yj. scelto fra :
in cui n3 è un intero da 0 a 3;
in cui nf' è un intero da 1 a 6 preferibilmente da 2 a 4;
in cui R1f = H, CH3 e nf è un intero da 1 a 6; preferibilmente da 2 a 4.
Questi composti contenenti un gruppo -ONO2 legato covalentemente alla molecola mediante uno dei ponti bivalenti di collegamento qui sopra indicati, sono preparati come descritto nella domanda di brevetto WO 95/30641 a nome della Richiedente, qui integralmente incorporata per riferimento.
Nelle composizioni secondo la presente invenzione possono utilizzarsi anche uno i più isomeri (anche gli isomeri ottici) quando sono possibili, dei composti sopra descritti.
I sali dei composti contengono almeno una mole di ione nitrato/mole di composto. Preferibilmente il rapporto tra le moli di ione nitrato e del precursore é unitario. Si ottengono sali con rapporto molare superiore quando nella molecola sono presenti altri gruppi amminici sufficientemente basici da poter essere salificati.
I sali della presente invenzione sono formulati nelle corrispondenti composizioni farmaceutiche secondo le tecniche ben note nel ramo, unitamente agli usuali eccipienti; si veda ad esempio il volume "Remington's Pharmaceutical Sciences I5a Ed . "
I precursori dei sali appartenenti alle classi sopra menzionate si preparano secondo i metodi descritti nel Merck Index 14a Ed., qui integralmente incorporato per riferimento.
I sali della presente invenzione sono ottenibili secondo uno dei seguenti metodi.
Se la sostanza da salificare é disponibile come base libera o come un sale corrispondente solubile in un solvente organico, che preferibilmente non contiene gruppi ossidrilici, ad esempio acetonitrile, acetato di etile, tetraidrofurano ecc., il sale viene preparato sciogliendo la sostanza nel solvente ad una concentrazione preferibilmente uguale o superiore al 10% p/v, aggiungendo la quantità di acido nitrico concentrato corrispondente alle moli di gruppi amminici salificabili presenti nel composto. L'acido nitrico é preferibilmente diluito nel medesimo solvente. Preferibilmente durante e dopo l'aggiunta si raffredda a temperature comprese tra 20°C e 0°C. Il prodotto viene generalmente recuperato per filtrazione e lavato con il solvente.
Se invece la sostanza é poco solubile, oppure é disponibile nella forma di un sale poco solubile nei solventi sopra menzionati, si possono impiegare le corrispondenti miscele con solventi ossidrilati. Esempi di tali solventi sono alcool metilico, alcool etilico ed acqua. La precipitazione può venire accellerata diluendo la miscela così ottenuta, dopo l'aggiunta di acido nitrico, con un solvente apolare.
Se il prodotto di partenza é salificato con acido cloridrico é possibile preparare il sale con acido nitrico aggiungendo direttamente alla soluzione del composto argento nitrato. Dopo aver filtrato il cloruro di argento, la soluzione viene concentrata e raffreddata per recuperare il sale nitrato .
Se il prodotto di partenza é un sale, si può anche liberare la base corrispondente per trattamento con una soluzione satura di bicarbonato o carbonato sodico o potassico, oppure con una soluzione diluita di sodio o potassio idrato. La base viene poi estratta con un adatto solvente organico (ad es. solventi alogenati, esteri, eteri), che viene poi essiccato. Si evapora la soluzione organica e si procede secondo i metodi di preparazione precedenti, sciogliendo la base in acetonitrile o negli altri solventi sopra menzionati.
I composti e composizioni della presente invenzione possono essere utilizzati per applicazioni sistemiche, ad esempio possono essere somministrati per via orale, ad es. espettoranti, intramuscolare, endovenosa, ecc; oppure possono essere utilizzati per applicazioni non sistemiche, ad esempio sotto forma di aerosol o applicazioni topiche. In generale i composti dell'invenzione trovano applicazione negli stessi campi dei precursori.
I dosaggi dei farmaci dell'invenzione sono quelli tipici dei precursori, tuttavia poiché i prodotti dell'invenzione mostrano un miglioramento terapeutico superiore a quello dei precursori, essi possono essere utilizzati anche in dosi superiori senza dare gli effetti collaterali che darebbero invece i precursori.
Altre applicazioni dei prodotti dell'invenzione sono come tocolitici (antispastici), per esempio antispastici della muscolatura uterina, antispastici della muscolatura intestinale; antistaminici (antiallergici) per es. per applicazioni oculari; antitussivi. Si possono applicare per via sistemica o non, come indicato sopra, oppure anche nella forma di composizioni oftalmiche, quali colliri, ecc.
I seguenti esempi vengono dati al solo scopo di illustrare l'invenzione e non costituiscono una limitazione della medesima.
ESEMPIO 1
Preparazione del sale Ambroxol nitrato
Si prepara una soluzione di Ambroxol (4 g, 20,6 mmoli) sciogliendo in una miscela di acetonitrile (30 mi) e tetraidrofurano (10 mi). Si aggiunge a freddo (4°C) acido nitrico diluito in acetonitrile (3,5 mi prelevati da una soluzione ottenuta aggiungendo a 2,7 mi di acido nitrico 65% e portando al volume finale di 10 mi con acetonitrile). Dopo 30 minuti si aggiunge lentamente, alla medesima temperatura (+ 4°C) etere etilico (100 mi). Si forma un precipitato che viene filtrato, lavato con etere etilico e seccato sotto vuoto. Si ottiene un solido amorfo bianco che all'analisi elementare risulta corrispondere a Ambroxol nitrato.
ESEMPIO 2
Preparazione del sale Salbutamolo nitrato
Partendo da una soluzione di Salbutamolo (4 g, 16,7 mmoli) in acetonitrile (30 mi) e .tetraidrofurano (10 mi) e utilizzando 4 mi di soluzione di acido nitrico in acetonitrile e la medesima procedura dell'esempio 1, si ottiene un solido amorfo che all'analisi elenmentare corrisponde al Salbutamolo nitrato .
PROVE FARMACOLOGICHE ESEMPIO 3
Studi di tossicità acuta dei sali dell'invenzione carbossimetilcellulosa 2% in peso.
La tossicità acuta dei sali é stata valutata per somministrazione orale di una dose singola crescente dei composti a gruppi di 10 topi ciascuno.
Gli animali sono stati tenuti sotto osservazione per 14 giorni, riportando l'incidenza di letalità e la comparsa di sintomatologia tossica.
Anche dopo somministrazione di una dose di 100 mg/Kg non si é evidenziato alcun segno di tossicità apparente.
ESEMPIO 4
Studio deali effetti del Salbutamolo e Salbutamolo nitrato sulla broncocostrizione sperimentale nella cavia
Gli animali venivano preparati seguendo il metodo di Del Soldato e Al., J. Pharmacol. Methods 5279 1981 per la rilevazione dell'attività cardiorespiratoria. Agli animali veniva iniettata per via endovenosa 0,1 mi di una soluzione salina di capsaicina (1 μg/Kg). Per 15 minuti (5 minuti prima e 10 minuti dopo la capsaicina) il Salbutamolo (0,3 nmoli/min), il corrispondente sale nitrato (0,3 nmoli/min) o il solo veicolo sono stati somministrati per infusione endovenosa.
La variazione dell'aria fidale prima e dopo la somministrazione di capsaicina veniva misurata mediante un apparato di Konzett modificato come descritto nella precedente pubblicazione di Del Soldato, connesso a un sistema poligrafico.
elettrocardiografico secondo le comuni metodiche. I risultati sono riportati in Tabella I. Il valore medio della frequenza cardiaca a seguito della somministrazione del veicolo era di 188 7 battiti al minuto. Le risposte sono espresse come valori percentuali rispetto al controllo.
Come indicato in Tabella, il Salbutamolo nitrato risulta ugualmente potente nell'inibire la risposta broncocostrittiva indotta da capsaicina, ma meglio tollerato {nessuna risposta tachicardica) rispetto al Salbutamolo stesso.
TABELLA I

Claims (14)

  1. RIVENDICAZIONI 1. Sali nitrati di composti scelti tra i seguenti: Salbutamolo avente formula (I)
    Cetrizina avente formula (II)
    Loratidina avente formula (III)
    Terfenadina avente formula (IV)
    Emedastina avente formula (V)
    Ketotifene avente formula (VI)
    Nedocromil avente formula (VII)
    Ambroxolo avente formula (Vili)
    Bromexina avente formula (IX)
    Destrometorfano avente formula (X)
  2. 2. Sali nitrati secondo la rivendicazione 1 in cui i composti sono Salbutamolo Cetirizina, Emedastina, Ambroxolo.
  3. 3 . Sali nitrati secondo le rivendicazioni 1-2, in cui i composti contengono uno o più gruppi -ONO2 legati covalentemente alla molecola mediante uno dei seguenti ponti di collegamento bivalenti: YO in cui Y è un alchilene C1-C20 lineare o ramificato quando possibile, preferibilmente da 2 a 5 atomi di carbonio, o un cicloalchilene da 5 a 7 atomi di carbonio eventualmente sostituito; Y3 scelto fra:
    in cui nf' è un intero da 1 a 6 preferibilmente da 2 a 4;
    in cui R1f = H, CH3 e nf è un intero da 1 a 6; preferibilmente da 2 a 4.
  4. 4. Sali nitrati secondo le rivendicazioni 1-3 contenenti uno o più isomeri dei composti indicati.
  5. 5. Sali secondo le rivendicazioni 1-4, in cui i sali di detti composti contengono almeno una mole di ione nitrato/mole di composto.
  6. 6. Composizioni farmaceutiche dei sali nitrati secondo le rivendicazioni 1-5.
  7. 7. Sali nitrati e composizioni farmaceutiche secondo le rivendicazioni 1-6 per uso come medicamento.
  8. 8. Uso dei sali e delle composizioni secondo la rivendicazione 7 per la preparazione di medicamenti per il trattamento di patologie del sistema respiratorio.
  9. 9. Uso dei sali e delle composizioni secondo la rivendicatocolitici .
  10. 10. Uso dei sali e delle composizioni secondo la rivendicazione 7 per la preparazione di medicamenti per uso come antiallergici, preferibilmente per applicazioni oculari.
  11. 11. Processo per la preparazione dei sali nitrati secondo le rivendicazioni da 1 a 5 in cui, quando la sostanza da salificare é disponibile come base o come un sale corrispondente solubile in un solvente organico che non contiene gruppi ossidrilici, il sale viene preparato sciogliendo la sostanza nel solvente ad una concentrazione uguale o superiore al 10% p/v, aggiungendo la quantità di acido nitrico concentrato corrispondente alle moli di gruppi amminici salificabili presenti nel composto, raffreddando durante e dopo l'aggiunta a temperature comprese tra 20°C e 0°C e recuperando il prodotto per filtrazione .
  12. 12. Processo secondo la rivendicazione 11 in cui se la sostanza é poco solubile o é disponibile nella forma di un sale poco solubile nei solventi sopra menzionati, si impiegano le corrispondenti miscele con solventi ossidrilati e la precipitazione viene accellerata diluendo la miscela così ottenuta, dopo l'aggiunta di acido nitrico, con un solvente apolare.
  13. 13. Processo secondo le rivendicazioni 11-12 in cui se il il sale con acido nitrico viene preparato aggiungendo direttamente alla soluzione del composto argento nitrato, filtrando il cloruro di argento, la soluzione concentrata e raffreddata per recuperare il sale nitrato.
  14. 14. Processo per la preparazione dei sali nitrati secondo le rivendicazioni da 1 a 5 in cui se il prodotto di partenza é un sale, si libera la base corrispondente per trattamento con una soluzione satura di bicarbonato o carbonato sodico o potassico o con una soluzione diluita di sodio o potassio idrato, estraendo la base con un adatto solvente organico, e seguendo i metodi per preparare il sale nitrato di cui alle rivendicazioni 11 o 12.
IT1998MI001743A 1998-07-28 1998-07-28 Sali dell'acido nitrico con farmaci attivi nel trattamento dipatologie del sistema respiratorio IT1303671B1 (it)

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IT1998MI001743A IT1303671B1 (it) 1998-07-28 1998-07-28 Sali dell'acido nitrico con farmaci attivi nel trattamento dipatologie del sistema respiratorio
RU2001102262/04A RU2254330C2 (ru) 1998-07-28 1999-07-20 Кислотно-аддитивные нитратные соли соединений и фармацевтическая композиция
SI9930862T SI1098870T1 (sl) 1998-07-28 1999-07-20 Nitratna sol cetirizina
CNB998090425A CN1264828C (zh) 1998-07-28 1999-07-20 特殊药物的硝酸酯和硝酸盐
DK99938300T DK1098870T3 (da) 1998-07-28 1999-07-20 Nitratsalt af Cetirizin
IL14068599A IL140685A0 (en) 1998-07-28 1999-07-20 Nitric esters and nitrate salts of specific drugs
ES99938300T ES2252958T3 (es) 1998-07-28 1999-07-20 Nitratos de cetirizina.
AT99938300T ATE307796T1 (de) 1998-07-28 1999-07-20 Nitratsalz von cetirizine
JP2000562338A JP4455760B2 (ja) 1998-07-28 1999-07-20 特定の薬物の硝酸エステル及び硝酸塩
PCT/EP1999/005171 WO2000006531A2 (en) 1998-07-28 1999-07-20 Nitric esters and nitrate salts of specific drugs
AU52857/99A AU770313C (en) 1998-07-28 1999-07-20 Nitric esters and nitrate salts of specific drugs
BR9912375-4A BR9912375A (pt) 1998-07-28 1999-07-20 Sais de nitrato, composições farmacêuticas, uso de sais e composições, e, processo para preparação de sais de nitrato.
EP99938300A EP1098870B1 (en) 1998-07-28 1999-07-20 Nitrate salt of Cetirizine
HU0102706A HUP0102706A3 (en) 1998-07-28 1999-07-20 Nitric esters and nitrate salts of drugs
US09/743,808 US6410791B1 (en) 1998-07-28 1999-07-20 Nitric esters and nitrate salts of specific drugs
KR1020017000803A KR100687806B1 (ko) 1998-07-28 1999-07-20 특정약의 질산에스테르 및 질산염
DE69927977T DE69927977T2 (de) 1998-07-28 1999-07-20 Nitratsalz von Cetirizine
CA2338854A CA2338854C (en) 1998-07-28 1999-07-20 Nitric esters and nitrate salts of specific drugs
ZA200100457A ZA200100457B (en) 1998-07-28 2001-01-16 Nitric esters and nitrate salts of specific drugs.
US10/151,955 US6828342B2 (en) 1998-07-28 2002-05-22 Nitric esters and nitrate salts of specific drugs
US10/736,688 US7122539B2 (en) 1998-07-28 2003-12-17 Nitric esters and nitrate salts of specific drugs
AU2004201457A AU2004201457A1 (en) 1998-07-28 2004-04-07 Nitric esters and nitrate salts of specific drugs

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AU770313B2 (en) 2004-02-19
US20040132744A1 (en) 2004-07-08
CN1310702A (zh) 2001-08-29
US7122539B2 (en) 2006-10-17
HUP0102706A3 (en) 2003-08-28
JP2002521468A (ja) 2002-07-16
CN1264828C (zh) 2006-07-19
AU2004201457A1 (en) 2004-05-06
EP1098870B1 (en) 2005-10-26
DE69927977T2 (de) 2006-07-13
EP1098870A2 (en) 2001-05-16
HUP0102706A2 (hu) 2001-12-28
ITMI981743A0 (it) 1998-07-28
US6410791B1 (en) 2002-06-25
WO2000006531A2 (en) 2000-02-10
ATE307796T1 (de) 2005-11-15
JP4455760B2 (ja) 2010-04-21
AU770313C (en) 2004-10-14
KR100687806B1 (ko) 2007-02-28
BR9912375A (pt) 2001-04-17
CA2338854C (en) 2010-01-26
RU2254330C2 (ru) 2005-06-20
DK1098870T3 (da) 2006-03-06
ES2252958T3 (es) 2006-05-16
AU5285799A (en) 2000-02-21
ZA200100457B (en) 2002-01-16
US20030028026A1 (en) 2003-02-06
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IT1303671B1 (it) 2001-02-23
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WO2000006531A3 (en) 2000-06-15

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