ITMI981408A1 - Sali nitrati di farmaci antiipertensivi - Google Patents
Sali nitrati di farmaci antiipertensivi Download PDFInfo
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- ITMI981408A1 ITMI981408A1 IT98MI001408A ITMI981408A ITMI981408A1 IT MI981408 A1 ITMI981408 A1 IT MI981408A1 IT 98MI001408 A IT98MI001408 A IT 98MI001408A IT MI981408 A ITMI981408 A IT MI981408A IT MI981408 A1 ITMI981408 A1 IT MI981408A1
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- Prior art keywords
- carbon atom
- carbon atoms
- formula
- alb
- nitrate
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- 239000002220 antihypertensive agent Substances 0.000 title description 8
- 229940127088 antihypertensive drug Drugs 0.000 title description 3
- 229910052799 carbon Inorganic materials 0.000 claims description 36
- 150000001875 compounds Chemical class 0.000 claims description 36
- 125000004432 carbon atom Chemical group C* 0.000 claims description 33
- 150000001721 carbon Chemical group 0.000 claims description 31
- 239000000243 solution Substances 0.000 claims description 29
- 125000000623 heterocyclic group Chemical group 0.000 claims description 26
- 150000002823 nitrates Chemical class 0.000 claims description 22
- 150000003839 salts Chemical class 0.000 claims description 22
- 238000000034 method Methods 0.000 claims description 19
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 claims description 18
- 125000003118 aryl group Chemical group 0.000 claims description 18
- 239000002083 C09CA01 - Losartan Substances 0.000 claims description 16
- 229960004773 losartan Drugs 0.000 claims description 16
- KJJZZJSZUJXYEA-UHFFFAOYSA-N losartan Chemical compound CCCCC1=NC(Cl)=C(CO)N1CC1=CC=C(C=2C(=CC=CC=2)C=2[N]N=NN=2)C=C1 KJJZZJSZUJXYEA-UHFFFAOYSA-N 0.000 claims description 16
- 239000000203 mixture Substances 0.000 claims description 16
- 238000002360 preparation method Methods 0.000 claims description 16
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 15
- 229910017604 nitric acid Inorganic materials 0.000 claims description 14
- 206010020772 Hypertension Diseases 0.000 claims description 13
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- 238000011282 treatment Methods 0.000 claims description 12
- 239000000126 substance Substances 0.000 claims description 10
- -1 silver nitrate compound Chemical class 0.000 claims description 9
- 229920006395 saturated elastomer Polymers 0.000 claims description 8
- SQGYOTSLMSWVJD-UHFFFAOYSA-N silver nitrate Substances [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 claims description 8
- 239000002243 precursor Substances 0.000 claims description 7
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- 230000002526 effect on cardiovascular system Effects 0.000 claims description 6
- 125000000468 ketone group Chemical group 0.000 claims description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M sodium bicarbonate Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 6
- 125000001424 substituent group Chemical group 0.000 claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- 229910001961 silver nitrate Inorganic materials 0.000 claims description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 4
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- 125000003277 amino group Chemical group 0.000 claims description 3
- 239000010751 BS 2869 Class A2 Substances 0.000 claims description 2
- 239000002080 C09CA02 - Eprosartan Substances 0.000 claims description 2
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- 238000001816 cooling Methods 0.000 claims description 2
- 238000007865 diluting Methods 0.000 claims description 2
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- OROAFUQRIXKEMV-LDADJPATSA-N eprosartan Chemical compound C=1C=C(C(O)=O)C=CC=1CN1C(CCCC)=NC=C1\C=C(C(O)=O)/CC1=CC=CS1 OROAFUQRIXKEMV-LDADJPATSA-N 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- YCPOHTHPUREGFM-UHFFFAOYSA-N irbesartan Chemical group O=C1N(CC=2C=CC(=CC=2)C=2C(=CC=CC=2)C=2[N]N=NN=2)C(CCCC)=NC21CCCC2 YCPOHTHPUREGFM-UHFFFAOYSA-N 0.000 claims description 2
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- 238000001556 precipitation Methods 0.000 claims description 2
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
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Description
Descrizione dell'invenzione industriale
La presente invenzione riguarda composti e relative composizioni da utilizzarsi nella terapia e profilassi dell'ipertensione. Più in particolare riguarda l'uso di detti antiipertensivi per uso sistemico e distrettuale, particolarmente per l'area cardiovascolare. Più specificatamente la presente invenzione si riferisce a nuovi composti antiipertensivi aventi migliorata efficacia.
I composti noti nell'arte utilizzati nel trattamento dell'ipertensione hanno in generale limitata efficacia. Di solito il trattamento dell'ipertensione viene realizzato somministrando al paziente gli antiipertensivi in associazione con altri farmaci attivi sul sistema vascolare, come ad esempio calcio antagonisti, diuretici, beta bloccanti, ACE inibitori. Ad esempio gli antiipertensivi antagonisti dell'angiotensina (es. Losartan), i calcio antagonisti (es. le diidropiridine), i diuretici (ad es. i derivati tiazidici), i vasodilatatori diretti e indiretti (es. Minoxidil, Zaprinast) da soli non sono in grado di assicurare il successo della terapia.
Occorre inoltre sottolineare che alcuni antiipertensivi provocano effetti collaterali a carico dell'apparato respiratorio, quali broncocostrizione, dispnea. Ad esempio gli antiipertensivi usati nel trattamento dell'angina pectoris e delle aritmie cardiache, ad es. Timololo e Propanololo, danno gli effetti collaterali indicati.
Altri antiipertensivi inducono vasodilatazione attraverso inibizione delle fosfodiesterasi, e mostrano effetti collaterali a carico di apparati diversi (gastrointestinale, cardiovascolare, oculare, etc.). Si veda ad esempio Sildenafil e Zaprinast .
Era sentita l'esigenza di avere a disposizione composizioni attive nel trattamento delle patologie dell'ipertensione per uso sistemico e distrettuale, in particolare dell'area cardiovascolare, con profilo terapeutico migliorato. In particolare era sentita inoltre l'esigenza di disporre di farmaci antiipertensivi ad azione beta bloccante o antifosfodiesterasica che avessero minori effetti collaterali.
La Richiedente ha inaspettatamente e sorprendentemente trovato composti e composizioni farmaceutiche utilizzabili nel trattamento delle patologie dell'ipertensione per uso sistemico e distrettuale, in particolare dell'area cardiovascolare, con profilo terapeutico migliorato, e prive degli effetti collaterali dei farmaci antiipertensivi noti.
Costituisce un oggetto della presente invenzione sali nitrati di composti ad attività antiipertensiva, o loro composizioni farmaceutiche, per uso sistemico e distrettuale, particolarmente da utilizzarsi per l'area cardiovascolare, detti composti essendo caratterizzati dal fatto di contenere almeno un gruppo reattivo in grado di venire salificato, detti conmposti scelti tra le seguenti classi:
Classe (Alb):
valenza libera, così da formare in combinazione con l'atomo di carbonio in posizione 5 un gruppo chetonico,
RA1 assieme a RiA1 e gli atomi di carbonio in posizione 4 e 5 dell'anello eterociclico nel composto di formula (Alb), con
valenze libere, forma l'anello aromatico a 6 ato¬
mi di carbonio recante un gruppo -COOH:
( IXC ) ;
e gli atomi di carbonio in posizio¬
ne 4 e 5 dell'anello eterociclico della formula (Alb) forma l'anello aromatico recante un gruppo COOH (ixc),
RIAI con RIVAI e con l'atomo di carbonio in posizione 4 dell'anello eterociclico della formula (Alb) forma il seguente anello saturo a cinque atomi di carbonio:
valenza libera,
valenza libera con valenza libera forma un doppio
legame tra gli atomi di carbonio in posizione 4 e 5 nell'anello eterociclico della formula (Alb),
con e gli atomi di carbonio in posizione 4 e 5
dell'anello eterociclico della formula (Alb) forma l'anello aromatico recante un gruppo -COOH (IXc);
con l'atomo di car¬
bonio in posizione 4 dell'anello eterociclico della formula (Alb) forma l'anello saturo a cinque atomi di carbonio (ixd),
e gli atomi di carbonio in posizione 4 e 5
dell'anello eterociclico della formula (Alb) forma l'anello aromatico recante un gruppo -C00H (IXc),
entrambe valenze libere formano un doppio legame
tra gli atomi di carbonio in posizione 4 e 5 dell'anello eterociclico della formula (Alb);
noto come Valsartan;
Classe (A2):
i precursori di questa classe sono i seguenti:
uguali o diversi tra loro, sono H, CH3,
Nella formula
Nella formula può assumere i seguenti significati:
nella formula
riella formula (A3) :
n ed m, uguali o diversi tra loro, sono 0, 1;
Si con S2 e gli atomi di carbonio in posizione 2 e 3 dell'anello aromatico C6 dello stesso radicale (XIp) forma il seguente anello:
2
in cui:
[(*} atomo adiacente all'anello aromatico della formula XIpvir] ;;; ;;
A é un atomo di carbonio terziario e contemporaneamente W1 é valenza libera in modo da formare un doppio legame -CH=CH- tra A e l'atomo di carbonio in posizione 1', ;A nell'anello a 5 atomi (XIpVIII) é un atomo di carbonio terziario che reca un sostituente tale che con l'atomo di carbonio in posizione 1' e con uno dei due radicali Wi o W2, essendo l'altro radicale valenza libera, forma un anello aromatico a 6 atomi di carbonio come dalla seguente formula: ;; ;;
Wi = H, valenza libera, quando W1 é valenza libera ed A é un atomo di carbonio terziario come sopra definito si forma un doppio legame tra A e l'atomo di carbonio in posizione l', ;wi assieme a W2 l'atomo di carbonio in posizione 1' e il sostituente A forma un anello aromatico a 6 atomi di carbonio,-W2 = valenza libera, -0 che con Wi = valenza libera e l'atomo di carbonio in posizione 1' forma un gruppo chetonico, ;W2 assieme a wi, l'atomo di carbonio in posizione 1' e il sostituente A forma un anello aromatico a 6 atomi di carbonio,· ;;; ;; ;
che gli atomi di carbonio in posizione 1 ;e 6 dell'anello aromatico dello stesso radicale (xip) e con xB1 nella formula (A3) uguale a ossigeno, essendo contemporaneamente valenza libera, forma il seguente anello: ;;
S4 é un atomo di carbonio terziario che con gli atomi di carbonio in posizione 1 e 6 dell'anello aromatico del radicale (Xlp), e con i seguenti componenti della formula (A3): l'atomo uguale ad ossigeno ; forma il seguente ;anello.· ; ;;
Classe (A4): ;di questa classe fanno parte i seguenti gruppi di compo-Sti : ;(A4a): ;; ; ; ; ;;
Classe (A7): ;di questa classe fanno parte i seguenti gruppi di composti : ;(A7a): ; ; ; ;;
I composti preferiti nella classe (Aib) sono i seguenti: quando e libere che formano un doppio legame -CH=CH- con gli atomi di carbonio in posizione 4 e 5 dell'anello eterociclico della formula residuo di Losartan,· ;come in Losartan ma con valenza libera, in modo da formare in combinazione con l'atomo di carbonio in posizione 5 dell'anello eterociclico della formula (Alb) un gruppo chetonico, RJA1 con RIVA1 e con l'atomo di carbonio in posizione 4 dell'anello eterociclico sono tali da formare l'anello saturo a 5 atomi di carbonio (ixd), residuo di irbesartan; ;come in Losartan ma con assieme a RJA1 e gli atomi di carbonio in posizione 4 e 5 dell'anello eterociclico con RIVA1 ed RZIIA1 valenze libere, sono tali da formare il radicale aromatico recante un gruppo -C00H (iXc), residuo di Candesartaccorrle in Losartan ma con ;;; valenze libere formano un doppio legame tra gli atomi ;di carbonio in posizione 4 e 5 nell'anello eterociclico della formula (Alb), residuo di Eprosartan. ;I composti preferiti della classe A2 sono i seguenti: ;;; ; ;
v ;I composti preferiti della classe (A3) sono i seguenti: ; ; ; ; ;;
Nella Classe (A4) i composti preferiti sono i seguenti: (A4a): ;; ; ; ;;
I precursori dei sali appartenenti alle classi sopra menzionate si preparano secondo i metodi descritti nel "The Merck index 12a Ed." (1996), qui integralmente incorporato per riferimento. Il metodo di preparazione del Sildenafil é descritto nel brevetto G.B. 92480. Il metodo di preparazione del Zaprinast é descritto nel brevetto DE 2162096. ;Nelle composizioni secondo la presente invenzione possono utilizzarsi anche gli isomeri dei composti appartenenti alle classi sopra descritte. ;I sali dei composti appartenenti a queste classi 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 15a Ed." I dosaggi dei sali dell'invenzione nelle loro composizioni farmaceutiche sono uguali, e in generale inferiori a quelli dei loro precursori delle classi indicate. ;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 poi 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 sali nitrati possono venir ottenuti anche impiegando precursori delle classi descritte che contengano nella molecola un gruppo -0N02 legato mediante un ponte di collegamento preparato come descritto nella domanda di brevetto Europeo 759899 a nome della Richiedente qui integralmente incorporata per riferimento. ;I seguenti esempi vengono dati al solo scopo di illustrare l'invenzione e non costituiscono una limitazione della medesima. ;ESEMPIO 1 ;Preparazione del sale Timololo nitrato ;Ad una soluzione acquosa satura di bicarbonato di sodio (100 mi) viene aggiunto il sale timololo maleato (7 g). La miscela viene estratta con etile acetato (300 mi). La fase organica viene essiccata su sodio solfato e poi evaporata sotto vuoto, ottenendo la corrispondente base del Timololo (4,9 g) che viene sciolto in acetonitrile (25 mi). La soluzione raffreddata con ghiaccio viene trattata con una soluzione di acido nitrico 65% (1,08 mi) in acetonitrile (5 mi) e dopo 30 minuti sotto agitazione a freddo si riprende con etere etilico (100 mi) a dare un solido che viene filtrato, lavato con etere etilico e seccato sotto vuoto. Si ottengono 4,6 g di Timololo sale nitrato p.f. 115-116°C. ;; ;
ESEMPIO 2 ;Preparazione del sale Propanololo nitrato ;Ad una soluzione acquosa satura di bicarbonato di sodio (70 mi) viene aggiunto il sale Propanololo cloridrato (5 g). La miscela viene estratta con etile acetato (250 mi). La fase organica viene essiccata su sodio solfato e poi evaporata sotto vuoto, ottenendo la corrispondente base del Propanololo (4,2 g) che viene sciolto in acetonitrile/tetraidrofurano 5/2 (70 mi). La soluzione raffreddata con ghiaccio viene trattata con una soluzione di acido nitrico 65% (1,13 mi) in acetonitrile (10 mi) e dopo 30 minuti sotto agitazione a freddo si riprende con etere etilico (50 mi) a dare un solido che viene filtrato, lavato con etere etilico e seccato sotto vuoto. Si ottengono ;; ;;
ESEMPIO 3 ;Preparazione del sale Sildenafil nitrato ;Una soluzione di Sildenafil (7,7 g, 16,3 mmoli) in una miscela di acetonitrile (100 mi) e tetraidrofurano (40 mi) viene trattata con acido nitrico 65% (1,13 ml) sciolto in acetonitrile (10 ml). Dopo 30 minuti a 4°C, si concentra a piccolo volume per evaporazione a pressione ridotta e si aggiunge lentamente etere etilico (100 ml). Il precipitato formatosi viene filtrato, lavato con etere etilico ed essiccato sotto vuoto. Si ottiene un solido amorfo bianco (6,5 g). ;Analisi elementare (C22H31N7O7S) : ;; ;;
ESEMPIO 4 ;Preparazione del sale Valsartan nitrato ;Si prepara una soluzione di Valsartan (3,48 g, 8 mmoli) sciogliendo in una miscela di acetonitrile (30 mi) e tetraidrofurano (10 mi). Si aggiunge a freddo (4°C) acido nitrico diluito in acetonitrile (2 mi prelevati da una soluzione ottenuta aggiungendo a 2,7 mi di acido nitrico 65% in acetonitrile e portando al volume finale di 10 mi). 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 (3,1 g). ;Analisi elementare (C24H30N6O6): ;; ;;
ESEMPIO 5 ;Preparazione del sale Idralazina nitrato ;Idralazina cloridrato (3 g) viene aggiunta a una soluzione acquosa (50 mi) di carbonato di potassio. Si estrae con etile acetato (80 mi). Si lava la fase organica con acqua, si essicca su solfato di sodio e si evapora sotto vuoto. Il residuo (lg, 6,25 mmoli) viene sciolto in una miscela di acetonitrile (30 mi) e metanolo (20 mi). Si raffredda a 4°C e si aggiunge una soluzione di acido nitrico 65% (0,6 g, 6,24 mmoli) in acetonitrile (10 mi). Si forma un precipitato, di colore bianco, che viene filtrato e seccato sotto vuoto (lg, p.f. 237-243°C). Analisi elementare (C0H9N5O3): ; ;;
ESEMPIO 6 ;Preparazione del sale Nicardipina nitrato ;Una soluzione di Nicardipina cloridrato (0,1 g, 0,194 mmoli) in acetonitrile (20 mi) viene trattata al buio con argento nitrato (0,33 g, 0,194 mmoli). Tenendo sotto agitazione a temperatura ambiente per 30 minuti, si forma il precipitato sotto forma di un solido bianco. Si filtra, si concentra a metà volume a pressione ridotta, si raffredda a 4°C e si riprende con alcool etilico (20 mi). Si filtra il precipitato. Si essicca. Si ottiene un solido giallo (0,05 g, p.f. 193-198°C). ;Analisi elementare (C26H30N4O9): ;; ;;
ESEMPIO 7 ;Preparazione del sale Verapamil nitrato ;Una soluzione di Verapamil cloridrato (3,44 g, 7 mmoli) in una miscela di acetonitrile (50 mi) e tetraidrofurano (15 mi) viene trattata al buio con argento nitrato (1,19 g, 7 mmoli). Si tiene la soluzione sotto agitazione a temperatura ambiente, per un'ora, Il precipitato si forma lentamente, e viene filtrato alla fine. La soluzione viene concentrata a metà volume, si raffredda a 4°C e si filtra il precipitato che si forma. Dopo essicamento si ottiene un solido amorfo bianco (2,8 g). ;Analisi elementare (C27H39N3O7): ;; ;
ESEMPIO 8 ;Preparazione del sale amiloride nitrato ;Una soluzione di amiloride cloridrato (2 g, 7,5 mmoli) in metanolo {100 mi) é trattata con argento nitrato al buio (1,28 g, 7,5 mmoli). Si forma rapidamente un precipitato. Si lascia sotto agitazione per 30 minuti a temperatura ambiente. Alla fine si filtra il solido e la soluzione viene concentrata a pressione ridotta a metà del volume iniziale. Si riprende con etere etilico (50 mi) e, dopo raffreddamento a 4°C, si filtra il solido ottenuto. Dopo essiccamento si isola un solido (0,8 g, p.f. > 280°C). ;Analisi elementare (C6H9C1N8O4): ;; ;;
ESEMPIO 9 ;Studio degli effetti del Propanololo. Propanololo nitrato. Timololo e Timololo nitrato sulla broncocostrizione sperimentale nella cavia ;I composti alla dose di 10 mg/Kg e il corrispondente veicolo sono stati somministrati alle cavie (gruppi di 6 animali ciascuno) per via intraperitoneale per tre giorni consecutivi. ;Gli animali venivano preparati seguendo il metodo di Del Soldato et al., J. Pharmacol. Methods 52791981. 45 minuti più tardi agli animali veniva iniettata per via endovenosa 0,1 mi di una soluzione salina di capsaicina (1 μg/Kg). La variazione dell'aria tidale 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. ;Gli effetti dei composti e dei loro corrispondenti sali nitrati sulla broncocostrizione sperimentale indotta nella cavia dall'iniezione di capsaicina sono riportati in Tabella I. ;; ;;
ESEMPIO 10 ;Attività farmacologica del Sildenafil nitrato in confronto a Sildenafil ;I composti sono stati somministrati in soluzione fisiologiogica. Il gruppo controllo é stato trattato con il veicolo (soluzione fisiologica). ;L'attività vaso-rilasciante del Sildenafil nitrato é stata determinata usando il modello sperimentale di costrizione dei vasi deferenti prostatici,indotta da stimolazione elettrica submassimale secondo il metodo descritto da D.A. Taylor et al., J. Pharmacol. Exp. Ther. 224, 40-451983, in ratti trattati con Nw-nitro-L-arginina-methyl ester (L-NAME) come descritto da Ribeiro et al., Hypertension, 20, 298, 1992. Ratti Wistar maschi adulti (235-284 g) hanno ricevuto per 6 settimane nell'acqua da bere L-NAME ad una concentrazione di 60-70 mg/100 mi, equivalente ad una somministrazione giornaliera di circa 60 mg/Kg. Gli animali ricevevano per via sottocutanea una dose giornaliera dì 10 mg/Kg di Sildenafil nitrato, Sildenafil o veicolo, rispettivamente, per cinque giorni. Un'ora dopo l'ultimo trattamento, gli animali sono stati sacrificati ed é stata prelevata la porzione prostatica di vaso deferente, mantenuta in soluzione fisiologica a 37°C e contratta da stimolazione transmurale di campo (95% della stimolazione massima, 0,2 Hz). ;La riduzione delle risposte contrattive neurogeniche, risultanti entro 5 minuti dall'aggiunta della sostanza in esame alla concentrazione 10-6 M, viene espressa come misura dell'attività vasorilasciante. ;; ;;
Come é evidente dalla tabella, il sale nitrato é in grado di esercitare una attività miorilasciante in misura molto maggiore rispetto al composto di riferimento. ;E'stato anche studiato l'effetto di rilassamento dell'arteria cavernosa e dei corpi cavernosi umani (effetto vasodilatatore a livello periferico). E' stata utilizzata la tecnica descritta da R. G. Hempelmann et al., European Journal of Pharmacology 276, 277-280 (1995), utilizzando tessuti erettili provenienti da pazienti sottoposti ad intervento chirurgico. Le arterie cavernose sono state isolate e ripulite del tessuto connettivo circostante. Sono stati ricavati segmenti della lunghezza di circa 2 mm, montati in un miografo. ;Dopo la costruzione di una curva diametro/tensione, i preparati sono stati regolati su un diametro corrispondente al 90% di quello raggiunto in presenza di una pressione transluminale di 100 mm Hg; dopo un periodo di stabilizzazione di circa 60 minuti, é stata indotta una contrazione mediante somministrazione di adrenalina 3.10-6 M. Dopo 15 minuti é stata somministrata una dose pari a IO'6 M dei composti in esame ed é stata registrata la percentuale di rilassamento indotta dalla somministrazione del prodotto in esame. I risultati sono riportati in tabella III. ;Un'altra serie di esperimenti é stata condotta secondo il medesimo protocollo, su strips isolate di tessuto cavernoso di dimensioni di circa 3 X 3 X 5 mm sospese isometricamente, sotto applicazione di una tensione di 5-10 mN in bagni per organi isolati. I risultati sono riportati in Tabella IV ;; ; ;;
In entrambi i modelli sperimentali é riscontrabile un effetto di rilassamento della contrazione indotta da adrenalina sia in seguito a trattamento con Sildenafil, sia in seguito a somministrazione del donatore di ossido nitrico SIN-1. Il derivato oggetto della presente invenzione ha dimostrato un effetto superiore sia a Sildenafil di partenza che a SIN-l. ;ESEMPIO 11 ;Studio dell'attività antiipertensiva ed anti-anoiotensinica di Losartan nitrato a confronto con Losartan ;I composti sono stati somministrati in soluzione fisiologiogica. Il gruppo controllo é stato trattato con il veicolo (soluzione fisiologica). ;La capacità di Losartan nitrato di inibire l'ipertensione arteriosa é stata determinata usando due modelli sperimentali: L'ipertensione arteriosa indotta da L-NAME (si veda l'esempio precedente) e la contrazione muscolare indotta da angiotensina II. Nel primo esperimento ratti Wistar maschi adulti (235-284 g) hanno ricevuto acqua da bere per 6 settimane contenente L-NAME ad una concentrazione di 60-70 mg/100 mi, equivalente ad una somministrazione giornaliera di circa 60 mg/Kg. Gli animali ricevevano per via sottocutanea una dose giornaliera di 10 mg/Kg di Losartan nitrato, Losartan o veicolo, rispettivamente, per cinque giorni.Un'ora dopo l'ultimo trattamento, veniva determinata la pressione arteriosa sistemica per via caudale, come descritto in precedenza da Zatz, Lab. Anim. Sci., 42, 198, 1990. ;Nel secondo esperimento (contrazione indotta da Angiotensina II) é stato seguito il metodo descritto da P.C. Wong et al., Hypertension, 13“, 489-497, 1989- Segmenti di ileo isolato prelevato da cavia (300-350 g) sono stati messi a contatto con angiotensina II (10 mcg/ml), in presenza di veicolo, Losartan nitrato 10'6M e Losartan 10'6M. I risultati sono riportati in Tabella V. ;; ;;
Dalla Tabella si vede che il nitroderivato é in grado di inibire l'ipertensione indotta da L-NAME in maggior misura rispetto al prodotto di riferimento. Riguardo l'attività miorilassante, i due prodotti sono entrambi efficaci nell'inibire la contrazione indotta da Angiotensina II, ma il prodotto dell'invenzione mostra un'efficacia superiore. ;ESEMPIO 12 ;Studio dell'attività antiipertensiva e vaso-rilasciante di Minoxidil nitrato a confronto con.Minoxidil ;I composti sono stati somministrati in soluzione fisiologiogica. Il gruppo controllo é stato trattato con il veicolo (soluzione fisiologica). ;La capacità di Monixidil nitrato di inibire l'ipertensione arteriosa é stata determinata usando due modelli sperimentali: L'ipertensione arteriosa indotta da L-NAME (si veda l'esempio 10) e la contrazione vascolare indotta da stimolazione elettrica. Nel primo esperimento farmacologico i ratti sono stati trattati come descritto nell'esperimento farmacologico con L-NAME descritto nell'esempio 11. Nel secondo esperimento é stato seguito il metodo descritto da Taylor di cui all'esempio 10. La porzione prostatica di vaso deferente isolato prelevato da ratti (200-220 g) é stata mantenuta in soluzione fisiologica a 37°C e contratta da stimolazione transmurale di campo (95% della stimolazione massima, 0,2 Hz). ;La riduzione delle risposte contrattive neurogeniche, risultanti entro 5 minuti dall'aggiunta della sostanza in esame alla concentrazione 10-6 M, viene espressa come misura dell'attività vasorilasciante. ;; ;
Come é evidente dalla tabella VI, il sale nitrato di Minoxidil é in grado di inibire l'ipertensione indotta da L-NAME in misura maggiore rispetto al composto di riferimento. Per quanto riguarda l'attività vaso-rilasciante, i due prodotti sono efficaci entrambi nell'inibire la vasocostrizione indotta elettricamente . ;ESEMPIO 13 ;Studio dell'attività antiinertensiva e beta-adrenolitica di Timololo nitrato in confronto a Timololo ;Il profilo farmacologico di Timololo nitrato é stato determinato usando due modelli sperimentali: l'ipertensione arteriosa indotta da L-NAME e l'effetto inotropo-positivo indotto da isoprenalina. ;Nel primo esperimento l'attività antiipertensiva é stata studiata secondo il modello già descritto nell'esempio 11. ;Nel secondo esperimento é stato seguito il metodo descritto da Grodzinski et al., Arch. Int. Phramacodyn., 191, 133-141, 1971. L'atrio sinistro prelevato da cavia (300-350 g) é stato mantenuto a 32°C in soluzione fisiologica ipocalcica (1/3 della concentrazione normale) e stimolato da isoprenalina (10 mcg/ml). La riduzione dell'effetto inotropo-positivo (aumento della contrazione del muscolo cardiaco) a seguito del-1'aggiunta della sostanza in esame alla concentrazione di 10-6M viene espressa come misura dell'attività beta-adrenolitica. ; ;;
Come é evidente dalla tabella VII, il sale nitrato del Timololo é in grado di inibire l'ipertensione indotta da L-NAME in misura maggiore rispetto al Timololo. Per quanto riguarda l'attività adrenolitica, i due prodotti sono entrambi efficaci nell'inibire l'effetto inotropo-positivo indotto da isoprenalina, ma il prodotto dell'invenzione mostra un'efficacia superiore. ;ESEMPIO 14 ;Studio dell'attività antiinertensiva e calcio antagonista del sale nitrato di Nicardipina in confronto alla Nicardipina Il profilo farmacologico di Nicardipina nitrato é stato determinato utilizzando due modelli sperimentali: l'ipertensione arteriosa indotta da L-NAME e la contrazione muscolare indotta da cloruro di calcio. ;Nel primo esperimento l'attività antiipertensiva é stata studiata secondo il modello già descritto nell'esempio 11. ;Nel secondo esperimento, il modello sperimentale di contrazione ileale indotta da cloruro di calcio, é secondo il metodo descritto da M.J. Spedding, J. Pharmacology 83, 211-220, 1984. Un segmento di ileo prelevato da cavia (300-350 g) era mantenuto a 37°C in soluzione fisiologica priva di calcio e stimolato da cloruro di calcio (20 mcg/ml). La riduzione della risposta contratturante, a seguito dell'aggiunta della sostanza in esame in modo da avere una concentrazione 10'* M, é la misura dell'attività calcio antagonista.
Come é evidente dalla Tabella, il sale nitrato é in grado di inibire l'ipertensione indotta da L-NAME in misura maggiore rispetto alla Nicardipina. Per quanto riguarda l'attività calcio antagonista i due composti si sono rivelati entrambi efficaci nell'inibire l'effetto contratturante calcio-dipendente, anche se in misura diversa.
ESEMPIO 15
Studio dell'attività antiipertensiva e diuretica nel ratto del sale nitrato di Amiloride a confronto con Amiloride
Il profilo farmacologico di Amiloride nitrato é stato determinato utilizzando due modelli sperimentali: l'ipertensione arteriosa indotta da L-NAME e la contrazione muscolare indotta da cloruro di calcio e l'effetto diuretico.
Nel primo esperimento l'attività antiipertensiva é stata studiata secondo il modello già descritto nell'esempio 11.
Nel secondo esperimento, l'effetto diuretico é stato seguito secondo il metodo descritto da W. L. Lipschwitz et al. J. Pharmacol . Exp. Ther., 79, 97-110, 1943. Gruppi di 6 ratti (200-220 g) ciascuno, stabulati in gabbie metaboliche ed idratati con acqua distillata (25 ml/Kg p.o.), venivano iniettati sotto cute con Amiloride nitrato (10 mg/Kg), Amiloride (10 mg/Kg) o veicolo. Il volume dell'urina é stato raccolto durante un periodo di 6 ore, misurato in mi ed espresso come variazione percentuale rispetto al volume di urina dei controlli.
Come é evidente dalla tabella IX, il sale nitrato di Amiloride é in grado di inibire l'ipertensione indotta da L-NAME, a differenza del composto non salificato. Per quanto riguarda l'attività vaso-rilasciante, i due composti hanno dimostrato attività diuretica simile.
ESEMPIO 16
Studi di tossicità acuta dei sali di Sildenafil e Zaprinast con acido nitrico
I due prodotti sono stati somministrati in sospensione di carbossimetilcellulosa 1-2%.
La tossicità acuta dei sali sopra indicati é stata valutata per somministrazione orale di una dose singola crescente del 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 50 mg/Kg non si é evidenziato alcun segno di tossicità apparente.
ESEMPIO 17
Studi di tossicità gastrica dei sali di Sildenafil e Zaprinast con acido nitrico a confronto con i precursori
Ratti Sprague-Dawley maschi, a digiuno da 24 ore, sono stati trattati i.p. con Sildenafil, Zaprinast, e con i relativi sali nitrati. 30 minuti più tardi agli animali é stato somministrato par via orale 1 mi di etanolo al 50%.
Un'ora dopo gli animali sono stati sacrificati. Dopo aver prelevato lo stomaco, il tessuto é stato esaminato macroscopicamente da un ricercatore ignaro del trattamento al quale i topi erano stati sottoposti, per verificare la presenza di lesioni come descritto da Gretzer et al. (Br. J. Pharmacol. 123, 927, 1998).
I risultati sono riportati in tabella X
Come si rileva dalla tabella, i ratti trattati con Sildenafil o Zaprinast presentavano un aggravamento della patologia a carico dell'apparato gastrointestinale rispetto ai controlli. Invece la tossicità gastrica dei sali nitrati corrispondenti era inferiore a quella del gruppo controllo.
Claims (1)
- RIVENDICAZIONI 1 . sali nitrati dei composti scelti tra le seguenti classi: Classe (A1b):binazione con l'atomo di carbonio in posizione 5 un gruppo chetonico, RA1 assieme a R1A1 e gli atomi di carbonio in posizione 4 e 5 dell'anello eterociclico nel composto di formula (Alb), con valenze libere, forma l'anello aromatico a 6 atomi di carbonio recante un gruppo -COOH:e gli atomi di carbonio in posizione 4 5 dell'anello eterociclico della formula (Alb) forma l'anello aromatico recante un gruppo COOH (IXC), e con l'atomo di carbonio in posizione 4 dell'anello eterociclico della formula (Alb) forma il seguente anello saturo a cinque atomi di carbonio: dop¬ pio legame tra gli atomi di carbonio in posizione 4 e 5 nell'anello eterociclico della formula (Alb), e gli atomi di carbonio in posizione 4 e 5 dell'anello eterociclico della formula (Alb) forma l'anello aromatico recante un gruppo -COOH (IXc); RIVA1 = valenza libera, assieme a con l'atomo di carbonio in posizione 4 dell'anello eterociclico della formula (Alb) forma l'anello saturo a cinque atomi di carbonio (IXd), e gli atomi di carbonio in posizione 4 e 5 dell'anello eterociclico della formula (Alb) forma l'anello aromatico recante un gruppo -COOH (IXc), entrambe valenze libere formano un doppio legame tra gli atomi di carbonio in posizione 4 e 5 dell'anello eterociclico della formula (Alb);Il precursore della classe (Ale) é noto come Vàlsartan; Classe A2):n ed m, uguali o diversi tra loro, sono 0, 1;A é un atomo di carbonio terziario e contemporaneamente Wi é valenza libera in modo da formare un doppio legame tra A e l'atomo di carbonio in posizione 1', A nell'anello a 5 atomi (XIpVI1) é un atomo di carbonio terziario che reca un sostituente tale che con l'atomo di carbonio in posizione 1' e con uno dei due radicali W1 o W2, essendo l'altro radicale valenza libera, forma l'anello aromatico a 6 atomi di carbonio come dalla seguente formulaWl = H, valenza libera, quando Wi é valenza libera ed A é un atomo di carbonio terziario come sopra definito si forma un doppio legame tra A e l'atomo di carbonio in posizione 1'; Wl assieme a W2 l'atomo di carbonio in posizione 1' e il sostituente A forma un anello aromatico a 6 atomi di carbonio; W2 = valenza libera, che con Wl = valenza libera e l'atomo di carbonio in posizione 1' forma un gruppo chetonico; W2 assieme a Wl, l'atomo di carbonio in posizione 1' e il sostituente A forma un anello aromatico a 6 atomi di carbonio; .che gli atomi di carbonio in posizione 1 e 6 dell'anello aromatico dello stesso radicale (XIp) e con nella formula (A3) uguale a ossigeno, essendo contemporaneamente m = n = 1 e RVIIB1 valenza libera, forma il seguente anello:S4 é un atomo di carbonio terziario che con gli atomi di carbonio in posizione 1 e 6 dell'anello aromatico del radicale (XIp), e con i seguenti componenti della formula (A3): l'atomo di carbonio il radicaleuguale ad ossigeno (m = 1), e R'niBi con RVIBI valenze libere, forma il seguente anello:2. Sali nitrati secondo la rivendicazione 1 dei seguenti composti della classe (Alb):lenze libere che formano un doppio legame -CH=CH- con gli atomi di carbonio in posizione 4 e 5 dell'anello eterociclico della formula residuo di Losartan; come in Losartan ma con valenza libera, in modo da formare in combinazione con l'atomo di carbonio in posizione 5 dell'anello eterociclico della formula (Alb) un gruppo chetonico, e con l'atomo di carbonio in posizione 4 dell'anello eterociclico sono tali da formare l'anello saturo a 5 atomi di carbonio (IXd), residuo di Irbesartan; come in Losartan ma cone gli atomi di carbonio in posizione 4 e 5 dell'anello eterociclico con valenze libere, sono tali da formare il radicale aromatico recante un gruppo -C00H (IXc), residuo di Candesartan; come in Losartan ma con Xvalenze libere formano un doppio legame tra gli atomi di carbonio in posizione 4 e 5 nell'anello eterociclico della formula (Alb), residuo di Eprosartan. 3. Sali nitrati secondo la rivendicazione 1 dei seguenti composti della classe (A3):come in Carteololo, ma in RIVB1 = (XlpVIII) A= -CH2-, B = -COCH2-, Wl = W2 = H, residuo di Levobunololo; come in Carteololo ma con RXB1 = H e in RIVB1 = (XIpVIII) A é un atomo di carbonio terziario e Wl valenza libera, in modo da formare un doppio legame -CH=CH- tra A e l'atomo di carbonio in posizione 1' di (XIpVII), W2 = CH3, residuoν 45. 6.7. Sali nitrati secondo le rivendicazioni 1-6 contenenti uno o più isomeri di detti composti. 8. Sali secondo le rivendicazioni 1-7, in cui i sali di detti composti contengono almeno una mole di ione nitrato/mole di composto. 9. Composizioni farmaceutiche dei sali nitrati secondo le rivendicazioni 1-8. 10. Sali nitrati e composizioni farmaceutiche secondo le rivendicazioni 1-9 per uso come medicamento. 11. Uso dei sali e delle composizioni secondo la rivendicazione 10 per la preparazione di medicamenti per il trattamento dell'ipertensione. 12 . Uso dei sali e delle composizioni secondo la rivendicazione 11 per la preparazione di medicamenti come cardiovascolari . 13. Processo per la preparazione dei sali nitrati secondo le rivendicazioni da 1 a 8 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. 14. Processo secondo la rivendicazione 13 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. 15. Processo secondo le rivendicazioni 13-14 in cui se il prodotto di partenza,é salificato con acido cloridrico, 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. 16. Processo per la preparazione dei sali nitrati secondo le rivendicazioni da 1 a 8 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 13 o 14.
Priority Applications (18)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IT1998MI001408A IT1301759B1 (it) | 1998-06-19 | 1998-06-19 | Sali nitrati di farmaci antiipertensivi |
DE69922001T DE69922001T2 (de) | 1998-06-19 | 1999-06-15 | Salpetersäuresalze von antihypertensiven arzneimitteln |
CN99807516A CN1315945A (zh) | 1998-06-19 | 1999-06-15 | 抗高血压药物的硝酸盐 |
IL13922699A IL139226A0 (en) | 1998-06-19 | 1999-06-15 | Nitrate salts of antihypertensive medicines |
PCT/EP1999/004138 WO1999067231A1 (en) | 1998-06-19 | 1999-06-15 | Nitrate salts of antihypertensive medicines |
ES99927990T ES2234265T3 (es) | 1998-06-19 | 1999-06-15 | Sales de nitrato de mecinas anti-hipertensivas. |
AU45139/99A AU770387B2 (en) | 1998-06-19 | 1999-06-15 | Nitrate salts of antihypertensive medicines |
RU2000131690/04A RU2235097C2 (ru) | 1998-06-19 | 1999-06-15 | Нитратные соли гипотензивных лекарственных средств |
HU0102719A HUP0102719A3 (en) | 1998-06-19 | 1999-06-15 | Nitrate salts of antihypertensive medicines |
JP2000555885A JP2002518492A (ja) | 1998-06-19 | 1999-06-15 | 抗高血圧医薬用硝酸塩 |
CA002335356A CA2335356A1 (en) | 1998-06-19 | 1999-06-15 | Nitrate salts of antihypertensive medicines |
BR9911305-8A BR9911305A (pt) | 1998-06-19 | 1999-06-15 | Sais de nitrato, processo para preparar o mesmo, composições farmacêuticas, e, uso dos mesmos |
AT99927990T ATE282600T1 (de) | 1998-06-19 | 1999-06-15 | Salpetersäuresalze von antihypertensiven arzneimitteln |
KR10-2000-7014179A KR100460714B1 (ko) | 1998-06-19 | 1999-06-15 | 항고혈압제의 질산염 |
EP99927990A EP1087953B1 (en) | 1998-06-19 | 1999-06-15 | Nitrate salts of antihypertensive medicines |
US09/719,164 US6645965B1 (en) | 1998-06-19 | 1999-06-15 | Nitrate salts of antihypertensive medicines |
ZA200006136A ZA200006136B (en) | 1998-06-19 | 2000-10-30 | Nitrate salts of antihypersensive medicines. |
US10/671,746 US20040147575A1 (en) | 1998-06-19 | 2003-09-29 | Nitrate salts of antihypertensive medicines |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
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IT1998MI001408A IT1301759B1 (it) | 1998-06-19 | 1998-06-19 | Sali nitrati di farmaci antiipertensivi |
Publications (2)
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ITMI981408A1 true ITMI981408A1 (it) | 1999-12-19 |
IT1301759B1 IT1301759B1 (it) | 2000-07-07 |
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IT1998MI001408A IT1301759B1 (it) | 1998-06-19 | 1998-06-19 | Sali nitrati di farmaci antiipertensivi |
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US (2) | US6645965B1 (it) |
EP (1) | EP1087953B1 (it) |
JP (1) | JP2002518492A (it) |
KR (1) | KR100460714B1 (it) |
CN (1) | CN1315945A (it) |
AT (1) | ATE282600T1 (it) |
AU (1) | AU770387B2 (it) |
BR (1) | BR9911305A (it) |
CA (1) | CA2335356A1 (it) |
DE (1) | DE69922001T2 (it) |
ES (1) | ES2234265T3 (it) |
HU (1) | HUP0102719A3 (it) |
IL (1) | IL139226A0 (it) |
IT (1) | IT1301759B1 (it) |
RU (1) | RU2235097C2 (it) |
WO (1) | WO1999067231A1 (it) |
ZA (1) | ZA200006136B (it) |
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-
1998
- 1998-06-19 IT IT1998MI001408A patent/IT1301759B1/it active IP Right Grant
-
1999
- 1999-06-15 RU RU2000131690/04A patent/RU2235097C2/ru not_active IP Right Cessation
- 1999-06-15 WO PCT/EP1999/004138 patent/WO1999067231A1/en active IP Right Grant
- 1999-06-15 EP EP99927990A patent/EP1087953B1/en not_active Expired - Lifetime
- 1999-06-15 IL IL13922699A patent/IL139226A0/xx unknown
- 1999-06-15 US US09/719,164 patent/US6645965B1/en not_active Expired - Fee Related
- 1999-06-15 KR KR10-2000-7014179A patent/KR100460714B1/ko not_active IP Right Cessation
- 1999-06-15 ES ES99927990T patent/ES2234265T3/es not_active Expired - Lifetime
- 1999-06-15 HU HU0102719A patent/HUP0102719A3/hu unknown
- 1999-06-15 CN CN99807516A patent/CN1315945A/zh active Pending
- 1999-06-15 DE DE69922001T patent/DE69922001T2/de not_active Expired - Fee Related
- 1999-06-15 AT AT99927990T patent/ATE282600T1/de not_active IP Right Cessation
- 1999-06-15 AU AU45139/99A patent/AU770387B2/en not_active Ceased
- 1999-06-15 CA CA002335356A patent/CA2335356A1/en not_active Abandoned
- 1999-06-15 JP JP2000555885A patent/JP2002518492A/ja active Pending
- 1999-06-15 BR BR9911305-8A patent/BR9911305A/pt not_active IP Right Cessation
-
2000
- 2000-10-30 ZA ZA200006136A patent/ZA200006136B/en unknown
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2003
- 2003-09-29 US US10/671,746 patent/US20040147575A1/en not_active Abandoned
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US6645965B1 (en) | 2003-11-11 |
WO1999067231A1 (en) | 1999-12-29 |
EP1087953B1 (en) | 2004-11-17 |
KR100460714B1 (ko) | 2004-12-09 |
AU4513999A (en) | 2000-01-10 |
HUP0102719A2 (hu) | 2001-12-28 |
US20040147575A1 (en) | 2004-07-29 |
IL139226A0 (en) | 2001-11-25 |
EP1087953A1 (en) | 2001-04-04 |
RU2235097C2 (ru) | 2004-08-27 |
KR20010093631A (ko) | 2001-10-29 |
IT1301759B1 (it) | 2000-07-07 |
AU770387B2 (en) | 2004-02-19 |
HUP0102719A3 (en) | 2002-11-28 |
DE69922001T2 (de) | 2005-11-03 |
DE69922001D1 (de) | 2004-12-23 |
JP2002518492A (ja) | 2002-06-25 |
CN1315945A (zh) | 2001-10-03 |
CA2335356A1 (en) | 1999-12-29 |
ATE282600T1 (de) | 2004-12-15 |
ES2234265T3 (es) | 2005-06-16 |
BR9911305A (pt) | 2001-10-23 |
ZA200006136B (en) | 2002-01-30 |
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