ITMI20110208A1 - HETEROCYCLES WITH ANTI-HYPERTENSIVE ACTIVITY - Google Patents
HETEROCYCLES WITH ANTI-HYPERTENSIVE ACTIVITY Download PDFInfo
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- ITMI20110208A1 ITMI20110208A1 IT000208A ITMI20110208A ITMI20110208A1 IT MI20110208 A1 ITMI20110208 A1 IT MI20110208A1 IT 000208 A IT000208 A IT 000208A IT MI20110208 A ITMI20110208 A IT MI20110208A IT MI20110208 A1 ITMI20110208 A1 IT MI20110208A1
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- 239000008223 sterile water Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 230000006441 vascular event Effects 0.000 description 1
- 229940124549 vasodilator Drugs 0.000 description 1
- 239000003071 vasodilator agent Substances 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
Description
Titolo: ETEROCICLI AD ATTIVITA’ ANTIIPERTENSIVA Title: HETEROCYCLES WITH ANTI-HYPERTENSIVE ACTIVITY
Descrizione Description
Campo dell’invenzione Field of invention
Il presente trovato riguarda molecole eterocicliche aventi attività antiipertensiva. In una forma di realizzazione, tali molecole eterocicliche hanno struttura tiazolidindionica. The present invention relates to heterocyclic molecules having antihypertensive activity. In one embodiment, such heterocyclic molecules have a thiazolidinedionic structure.
Stato dell’arte State of the art
L’ipertensione arteriosa à ̈ il maggiore fattore di rischio per patologie cardiovascolari. Non sempre le terapie attualmente utilizzate riescono tuttavia ad instaurare un regolare livello pressorio nei pazienti trattati, nonostante l’esistenza di numerosi approcci terapeutici, rivolti a differenti target farmacologici, che vengono spesso usati in combinazione. Esiste infatti una consistente popolazione di pazienti refrattari alle terapie note. Arterial hypertension is the major risk factor for cardiovascular diseases. However, the currently used therapies do not always manage to establish a regular pressure level in treated patients, despite the existence of numerous therapeutic approaches, aimed at different pharmacological targets, which are often used in combination. In fact, there is a large population of patients who are refractory to known therapies.
In aggiunta, la prevenzione di eventi cardiovascolari e cerebrovascolari in pazienti trattati farmacologicamente per l’ipertensione non à ̈ sempre efficace. In addition, the prevention of cardiovascular and cerebrovascular events in patients treated pharmacologically for hypertension is not always effective.
La ricerca di nuovi target farmacologici per il controllo della pressione arteriosa à ̈ quindi continuato negli anni. Nell’ultimo decennio, sono stati condotti vari studi al fine di meglio comprendere i meccanismi cellulari e molecolari che contribuiscono sia alla genesi della malattia ipertensiva sia all’instaurarsi del danno ai vari organi bersaglio. Sono stati così individuati nuovi meccanismi intracellulari che regolano positivamente o negativamente la pressione sanguigna. E’ stato dimostrato che topi cui mancava l’isoforma gamma della famiglia di fosfoinositido-3-chinasi (P13Kγ), che viene principalmente espressa nei leucociti e nei tessuti cardiovascolari, erano protetti dall’ipertensione indotta dalla somministrazione cronica di angiotensina II, il che suggerisce che l’inibizione di P13Kγ può essere un promettente target molecolare per una nuova terapia antiipertensiva. The search for new pharmacological targets for the control of blood pressure has therefore continued over the years. In the last decade, various studies have been conducted in order to better understand the cellular and molecular mechanisms that contribute both to the genesis of hypertensive disease and to the onset of damage to the various target organs. Thus, new intracellular mechanisms have been identified that positively or negatively regulate blood pressure. It was shown that mice lacking the gamma isoform of the phosphoinositido-3-kinase family (P13Kγ), which is mainly expressed in leukocytes and cardiovascular tissues, were protected from hypertension induced by chronic administration of angiotensin II , which suggests that P13Kγ inhibition may be a promising molecular target for a new antihypertensive therapy.
Sommario dell’invenzione Summary of the invention
Un oggetto della presente invenzione à ̈ quello di mettere a disposizione delle nuove molecole dotate di attività antiipertensiva. An object of the present invention is to make available new molecules endowed with antihypertensive activity.
Un ulteriore oggetto della presente invenzione à ̈ quello di mettere a disposizione molecole con attività inibitoria dell’isoforma P13Kγ di fosfoinositido-3-chinasi. A further object of the present invention is to provide molecules with inhibitory activity of the P13Kγ isoform of phosphoinositido-3-kinase.
Un ulteriore oggetto della presente invenzione à ̈ quello di mettere a disposizione una nuova terapia dell’ipertensione arteriosa che sia in grado di regolare efficacemente la pressione arteriosa in un paziente iperteso. A further object of the present invention is that of providing a new therapy for arterial hypertension which is capable of effectively regulating arterial pressure in a hypertensive patient.
Un ulteriore oggetto della presente invenzione à ̈ quello di mettere a disposizione una nuova terapia di prevenzione di eventi cardiovascolari o cerebro vascolari correlati ad ipertensione arteriosa. A further object of the present invention is to provide a new prevention therapy for cardiovascular or cerebral vascular events related to arterial hypertension.
Un ulteriore oggetto della presente invenzione à ̈ quello di mettere a disposizione una formulazione farmaceutica comprendente uno o più principi attivi dell’invenzione, unitamente ad eccipienti e veicoli farmaceuticamente accettabili. A further object of the present invention is to provide a pharmaceutical formulation comprising one or more active ingredients of the invention, together with pharmaceutically acceptable excipients and vehicles.
Tali oggetti sono raggiunti mettendo a disposizione molecole di formula (I): These objects are achieved by providing molecules of formula (I):
Y Y
H H.
N No.
X X
O OR
R1 z R1 z
R4 R4
A TO
R2 R3 R2 R3
(I) (THE)
in cui X Ã ̈ S, O oppure NH; where X is S, O or NH;
Y is O, S oppure NH; Y is O, S or NH;
Z is O, S oppure NH; Z is O, S or NH;
R1 Ã ̈ scelto nel gruppo che consiste in nitro, arile, eteroarile, alchile, eteroalchile, acile e alogeni; R2 Ã ̈ scelto nel gruppo che consiste in idrogeno, arile, eteroarile, alchile, eteroalchile, acile e alogeni; quando R1 e R2 sono parti di un ciclo, la struttura A Ã ̈ scelta nel gruppo che consiste in cicloalchile, eterocicloalchile, arile, eteroarile; R1 is selected from the group consisting of nitro, aryl, heteroaryl, alkyl, heteroalkyl, acyl and halogens; R2 is selected from the group consisting of hydrogen, aryl, heteroaryl, alkyl, heteroalkyl, acyl and halogens; when R1 and R2 are parts of a cycle, structure A is chosen from the group consisting of cycloalkyl, heterocycloalkyl, aryl, heteroaryl;
R3 Ã ̈ scelto nel gruppo che consiste in idrogeno, arile, eteroarile, alchile, eteroalchile, acile e alogeni; R3 is selected from the group consisting of hydrogen, aryl, heteroaryl, alkyl, heteroalkyl, acyl and halogens;
R4 Ã ̈ scelto nel gruppo che consiste in idrogeno, arile, eteroarile, alchile, eteroalchile; R4 is selected from the group consisting of hydrogen, aryl, heteroaryl, alkyl, heteroalkyl;
loro isomeri E e Z e loro sali farmaceuticamente accettabili, così come verrà meglio definito nella seguente “descrizione dettagliata dell’invenzione†e nelle annesse rivendicazioni, le cui definizioni formano parte integrante della presente descrizione. their E and Z isomers and their pharmaceutically acceptable salts, as it will be better defined in the following â € œdetailed description of the inventionâ € and in the attached claims, the definitions of which form an integral part of the present description.
Un ulteriore oggetto dell’invenzione sono le molecole di formula (I) come sopra definite per l’uso nella terapia dell’ipertensione arteriosa, così come una composizione farmaceutica che le contiene. A further object of the invention are the molecules of formula (I) as defined above for use in the therapy of arterial hypertension, as well as a pharmaceutical composition that contains them.
Breve descrizione delle figure Brief description of the figures
Figura 1: sono riportati gli effetti, ad uno e cinque giorni dalla somministrazione, della dose massima (40 mg*kg<-1>) di un composto rappresentativo dell’invenzione confrontati con quelli della molecola commerciale AS605240 (40 mg*kg<-1>), somministrati per via intravenosa; Figure 1: the effects, at one and five days after administration, of the maximum dose (40 mg * kg <-1>) of a representative compound of the invention are shown compared with those of the commercial molecule AS605240 (40 mg * kg < -1>), administered intravenously;
Figura 2: i grafici A e B mostrano gli effetti di abbassamento pressorio dose-dipendenti di un composto rappresentativo dell’invenzione, somministrato per via orale, in funzione dei giorni di trattamento; Figure 2: Graphs A and B show the dose-dependent blood pressure lowering effects of a representative compound of the invention, administered orally, as a function of treatment days;
Figura 3: i grafici A e B mostrano i livelli di pressione sanguigna nei topi P13Kγ+/+ e nei topi P13Kγ-/-in funzione dei giorni di trattamento; Figure 3: Graphs A and B show blood pressure levels in P13Kγ + / + and P13Kγ - / - mice as a function of treatment days;
Figura 4: i grafici A e B mostrano l’effetto ipotensivo in topi geneticamente modificati che esprimono un mutante di P13Kγ in cui la chinasi à ̈ inattiva (P13Kγ<kD/kD>); Figure 4: Graphs A and B show the hypotensive effect in genetically modified mice expressing a P13Kγ mutant in which the kinase is inactive (P13Kγ <kD / kD>);
Figura 5: i grafici A e B mostrano i livelli di pressione sanguigna in un modello murino in cui l’ipertensione era stata indotta mediante infusione cronica di angiotensina II (AngII); Figure 5: Graphs A and B show blood pressure levels in a mouse model in which hypertension was induced by chronic infusion of angiotensin II (AngII);
Figura 6: i grafici A e B mostrano i livelli di pressione sanguigna in un modello murino in cui l’ipertensione era stata indotta mediante infusione cronica di L-NAME, un inibitore di ossido-nitrico-sintasi; Figure 6: Graphs A and B show blood pressure levels in a mouse model in which hypertension was induced by chronic infusion of L-NAME, a nitric oxide synthase inhibitor;
Figura 7: il grafico mostra i livelli di pressione sanguigna in un modello murino di ratti spontaneamente ipertesi (RSI); Figure 7: The graph shows blood pressure levels in a mouse model of spontaneously hypertensive (RSI) rats;
Figura 8: il grafico riporta le resistenze periferiche totali, prima e dopo somministrazione del farmaco; Figure 8: the graph shows the total peripheral resistance, before and after drug administration;
Figura 9: i grafici A e B mostrano la variazione del diametro interno delle arterie mesenteriche perfuse; Figure 9: Graphs A and B show the variation in the internal diameter of the perfused mesenteric arteries;
Figura 10: la tabella mostra l’efficacia di inibizione delle diverse isoforme di PI3K da parte di un composto rappresentativo dell’invenzione. Figure 10: the table shows the efficacy of inhibition of the different isoforms of PI3K by a compound representative of the invention.
Descrizione dettagliata dell’invenzione Detailed description of the invention
La presente invenzione riguarda molecole di formula (I): The present invention relates to molecules of formula (I):
Y Y
H N H N
X X
O OR
R1 z R1 z
R4 R4
A TO
R2 R3 R2 R3
(I) (THE)
in cui X Ã ̈ S, O oppure NH; where X is S, O or NH;
Y is O, S oppure NH; Y is O, S or NH;
Z is O, S oppure NH; Z is O, S or NH;
R1 Ã ̈ scelto nel gruppo che consiste in nitro, arile, eteroarile, alchile, eteroalchile, acile e alogeni; R1 is selected from the group consisting of nitro, aryl, heteroaryl, alkyl, heteroalkyl, acyl and halogens;
R2 Ã ̈ scelto nel gruppo che consiste in idrogeno, arile, eteroarile, alchile, eteroalchile, acile e alogeni; R2 is selected from the group consisting of hydrogen, aryl, heteroaryl, alkyl, heteroalkyl, acyl and halogens;
quando R1 e R2 sono parti di un ciclo, la struttura A Ã ̈ scelta nel gruppo che consiste in cicloalchile, eterocicloalchile, arile, eteroarile; when R1 and R2 are parts of a cycle, structure A is chosen from the group consisting of cycloalkyl, heterocycloalkyl, aryl, heteroaryl;
R3 Ã ̈ scelto nel gruppo che consiste in idrogeno, arile, eteroarile, alchile, eteroalchile, acile e alogeni; R4 Ã ̈ scelto nel gruppo che consiste in idrogeno, arile, eteroarile, alchile, eteroalchile; R3 is selected from the group consisting of hydrogen, aryl, heteroaryl, alkyl, heteroalkyl, acyl and halogens; R4 is selected from the group consisting of hydrogen, aryl, heteroaryl, alkyl, heteroalkyl;
loro isomeri E e Z e loro sali farmaceuticamente accettabili. their E and Z isomers and their pharmaceutically acceptable salts.
Con il termine “arile†si intende preferibilmente un anello C6-C14 arile, eventualmente sostituito con uno o più gruppi nitro, ciano, ammino, mono- o di-C1-C3 alchilammino, C1-C5 alchile, idrossi, C1-C3 alcossi, carbossi, C1-C3 alcossicarbonile, aldeido, C1-C3 alchilcheto, alogeno; più preferibilmente un gruppo fenile o naftile, eventualmente sostituito come qui sopra indicato. The term â € œarylâ € preferably means a C6-C14 aryl ring, possibly substituted with one or more nitro, cyano, amino, mono- or di-C1-C3 alkylamino, C1-C5 alkyl, hydroxy, C1-C3 groups alkoxy, carboxy, C1-C3 alkoxycarbonyl, aldehyde, C1-C3 alkylketo, halogen; more preferably a phenyl or naphthyl group, optionally substituted as indicated above.
Con il termine “eteroarile†si intende preferibilmente un eterociclo aromatico con da 5 a 10 termini e comprendente da 1 a 3 eteroatomi scelti tra N, S oppure O, eventualmente sostituito con uno o più gruppi nitro, ciano, ammino, mono- o di-C1-C3 alchilammino, C1-C5 alchile, idrossi, C1-C3 alcossi, carbossi, C1-C3 alcossicarbonile, aldeido, C1-C3 alchilcheto, alogeno; più preferibilmente pirrolo, pirazolo, tiofene, tiazolo, imidazolo, piridina, pirazina, pirimidina, piridazina, chinolina, isochinolina, chinazolina, benzotiazolo, benzossazolo, benzopirazolo o benzimidazolo, eventualmente sostituiti come qui sopra indicato. The term `` heteroaryl '' preferably means an aromatic heterocycle with from 5 to 10 terms and comprising from 1 to 3 heteroatoms selected from N, S or O, possibly substituted with one or more nitro, cyano, amino, mono- or di-C1-C3 alkylamino, C1-C5 alkyl, hydroxy, C1-C3 alkoxy, carboxy, C1-C3 alkoxycarbonyl, aldehyde, C1-C3 alkylketo, halogen; more preferably pyrrole, pyrazole, thiophene, thiazole, imidazole, pyridine, pyrazine, pyrimidine, pyridazine, quinoline, isoquinoline, quinazoline, benzothiazole, benzoxazole, benzopyrazole or benzimidazole, possibly substituted as indicated above.
Con il termine “alchile†si intende preferibilmente un gruppo C1-C10 alchile, più preferibilmente C1-C5 alchile, lineare o ramificato, saturo o con da 1 a 3 insaturazioni, eventualmente sostituito con uno o più gruppi nitro, ciano, ammino, mono- o di-C1-C3 alchilammino, C1-C5 alchile, idrossi, C1-C3 alcossi, carbossi, C1-C3 alcossicarbonile, aldeido, C1-C3 alchilcheto, alogeno; ancora più preferibilmente metile, etile n-propile, isopropile, n-butile, tert-butile, pentile. The term â € œalkylâ € preferably means a C1-C10 alkyl group, more preferably C1-C5 alkyl, linear or branched, saturated or with 1 to 3 unsaturations, possibly substituted with one or more nitro, cyano, amino groups, mono- or di-C1-C3 alkylamino, C1-C5 alkyl, hydroxy, C1-C3 alkoxy, carboxy, C1-C3 alkoxycarbonyl, aldehyde, C1-C3 alkylketo, halogen; even more preferably methyl, ethyl n-propyl, isopropyl, n-butyl, tert-butyl, pentyl.
Con il termine “cicloalchile†si intende preferibilmente un gruppo C5-C10 cicloalchile, eventualmente sostituito con uno o più gruppi nitro, ciano, ammino, mono- o di-C1-C3 alchilammino, C1-C5 alchile, idrossi, C1-C3 alcossi, carbossi, C1-C3 alcossicarbonile, aldeido, C1-C3 alchilcheto, alogeno; più preferibilmente ciclopentile, cicloesile, cicloeptile. The term `` cycloalkyl '' preferably means a C5-C10 cycloalkyl group, possibly substituted with one or more nitro, cyano, amino, mono- or di-C1-C3 alkylamino, C1-C5 alkyl, hydroxy, C1-C3 groups alkoxy, carboxy, C1-C3 alkoxycarbonyl, aldehyde, C1-C3 alkylketo, halogen; more preferably cyclopentyl, cyclohexyl, cycloheptyl.
Con il termine “eteroalchile†o “eterocicloalchile†si intende preferibilmente un gruppo eterociclo come sopra definito legato ad un gruppo alchile o cicloalchile come sopra definito. The term â € œheteroalkylâ € or â € œheterocycloalkylâ € preferably means a heterocycle group as defined above linked to an alkyl or cycloalkyl group as defined above.
Con il termine “acile†si intende preferibilmente un gruppo C1-C10 alchilcheto. The term â € œacylâ € preferably refers to a C1-C10 alkyl group.
Molecole di formula (I) particolarmente preferite sono quelle in cui X à ̈ NH e Y à ̈ ossigeno. Ancora più preferibilmente, R4 à ̈ idrogeno. Particularly preferred molecules of formula (I) are those in which X is NH and Y is oxygen. Even more preferably, R4 is hydrogen.
I composti di formula (I) possono essere preparati secondo metodiche ben note al chimico organico. The compounds of formula (I) can be prepared according to methods well known to the organic chemist.
In particolare, un primo metodo per preparare i composti di formula (I) in cui X à ̈ NH e Y à ̈ ossigeno comprende la reazione di tiazolidin-2,4-dione con un’appropriata aldeide di formula (II): In particular, a first method for preparing the compounds of formula (I) in which X is NH and Y is oxygen comprises the reaction of thiazolidin-2,4-dione with an appropriate aldehyde of formula (II):
O OR
R1<Z>R1 <Z>
R R.
A 4 A 4
R2 R 3 R2 R 3
(II) (II)
in cui R1, R2, R3, R4, Z ed A sono come sopra definiti, in presenza di una base e a temperatura di riflusso del solvente, tipicamente tra 60°C e 120°C. wherein R1, R2, R3, R4, Z and A are as defined above, in the presence of a base and at the reflux temperature of the solvent, typically between 60 ° C and 120 ° C.
Analogamente, partendo in generale da un composto di formula (III): Similarly, starting in general from a compound of formula (III):
Y Y
X N H X N H
O OR
(III) (III)
in cui X e Y sono come sopra definiti, per reazione con un composto di formula (II) come sopra definito, si possono ottenere i composti di formula (I) dell’invenzione. wherein X and Y are as defined above, by reaction with a compound of formula (II) as defined above, the compounds of formula (I) of the invention can be obtained.
Come base si usa preferibilmente un’ammina quale ad esempio pirrolidina o acetato di un metallo alcalino, ad esempio acetato di potassio. An amine such as pyrrolidine or acetate of an alkali metal, for example potassium acetate, is preferably used as the base.
Secondo un’altra metodica, la reazione tra i composti di formula (II) ed i composti di formula (III) può essere condotta, in presenza di una base e di gel di silice, in forno a microonde. Preferibilmente, si utilizzerà una potenza tra 600 e 800 W. According to another method, the reaction between the compounds of formula (II) and the compounds of formula (III) can be carried out, in the presence of a base and silica gel, in a microwave oven. Preferably, a power between 600 and 800 W will be used.
I composti di formula (II) o di formula (III) sono commerciali o possono essere preparati secondo metodiche convenzionali, ben note all’esperto del settore. The compounds of formula (II) or formula (III) are commercial or can be prepared according to conventional methods, well known to those skilled in the art.
L’invenzione verrà ora illustrata per mezzo dei seguenti esempi, che sono mostrati a solo titolo descrittivo, ma non limitativo dell’invenzione. The invention will now be illustrated by means of the following examples, which are shown for descriptive purposes only, but not limitative of the invention.
Metodologia generale General methodology
Metodo A - 0,01 moli di tiazolidin-2,4-dione e 0,01 moli dell'appropriata aldeide o chetone di formula (II) sono dissolte in benzene (200 ml), viene aggiunta piperidina (0,01 mmole) e la risultante miscela viene messa sotto agitazione e riscaldata a temperatura di riflusso. Dopo 8 hr alla miscela di reazione si aggiunge acido acetico (0,01 mmole) e la reazione viene portata avanti fino alla raccolta della quantità stechiometrica di acqua in un separatore Dean Starck collegato al pallone di reazione. Dopo raffreddamento, dalla miscela di reazione precipita il prodotto grezzo (isomero Z) che viene filtrato, lavato con n-esano e cristallizzato da una miscela di etilacetato : n-esano (1:2 v:v). La resa di prodotto finale puro varia tra il 60-80 %. Method A - 0.01 moles of thiazolidine-2,4-dione and 0.01 moles of the appropriate aldehyde or ketone of formula (II) are dissolved in benzene (200 ml), piperidine (0.01 mmole) is added and the resulting mixture is stirred and heated to reflux temperature. After 8 hr acetic acid (0.01 mmole) is added to the reaction mixture and the reaction is carried on until the stoichiometric quantity of water is collected in a Dean Starck separator connected to the reaction flask. After cooling, the crude product (isomer Z) precipitates from the reaction mixture which is filtered, washed with n-hexane and crystallized from a mixture of ethyl acetate: n-hexane (1: 2 v: v). The yield of pure final product varies between 60-80%.
Metodo B - 0,012 moli di acetato di potassio anidro e 0,02 mol di tiazolidin-2,4-dione vengono sciolti a 100°C, in 15 minuti, in 100 ml di acido acetico glaciale. La temperatura della miscela di reazione viene portata a 75 °C e vengono aggiunte in una volta, 0,01 moli dell'opportuna aldeide o chetone di formula (II) disciolta in 100 ml di acido acetico glaciale. La miscela risultante viene riscaldata a 115°C per 45 minuti. Dopo raffreddamento, la soluzione viene versata su ghiaccio e lasciata riposare tutta la notte a temperatura ambiente. Il precipitato formatosi (isomero Z) viene raccolto per filtrazione, lavato con etanolo e seccato. La resa varia tra il 65-80%. Method B - 0.012 mol of anhydrous potassium acetate and 0.02 mol of thiazolidine-2,4-dione are dissolved at 100 ° C, in 15 minutes, in 100 ml of glacial acetic acid. The temperature of the reaction mixture is brought to 75 ° C and 0.01 moles of the suitable aldehyde or ketone of formula (II) dissolved in 100 ml of glacial acetic acid are added at one time. The resulting mixture is heated to 115 ° C for 45 minutes. After cooling, the solution is poured on ice and left to stand overnight at room temperature. The precipitate formed (isomer Z) is collected by filtration, washed with ethanol and dried. The yield varies between 65-80%.
Procedura al Microonde Microwave procedure
0,03 moli di tiazolidin-2,4-dione, 0,03 mmoli di piperidina e approssimativamente 100 mg di gel di silice attivato vengono mescolate in un vial di vetro delle dimensioni 2x12. Vengono aggiunte quindi 0,03 moli della opportuna aldeide e la miscela risultante viene sottoposta ad irradiazione a microonde alla potenza di 700 W per 6-8 minuti. Ogni 60 secondi di irradiazione la miscela viene raffreddata e rimescolata a fondo. Dopo quattro minuti, si aggiungono quindi 0,01 moli di acido acetico e la reazione viene monitorata per TLC ogni 60 secondi. Staccata la reazione, la miscela viene raffreddata a temperatura ambiente e cromatografata su colonna di gel di silice usando acetato di etile come eluente. Dalla fase organica, evaporata sotto vuoto, si ottiene il prodotto (isomero Z) con una resa del 70-80%. 0.03 mol of thiazolidine-2,4-dione, 0.03 mmol of piperidine and approximately 100 mg of activated silica gel are mixed in a 2x12 sized glass vial. 0.03 moles of the appropriate aldehyde are then added and the resulting mixture is subjected to microwave irradiation at the power of 700 W for 6-8 minutes. Every 60 seconds of irradiation the mixture is cooled and thoroughly stirred. After four minutes, 0.01 moles of acetic acid are then added and the reaction is monitored by TLC every 60 seconds. Once the reaction has been removed, the mixture is cooled to room temperature and chromatographed on a silica gel column using ethyl acetate as eluent. From the organic phase, evaporated under vacuum, the product (isomer Z) is obtained with a yield of 70-80%.
PARTE SPERIMENTALE EXPERIMENTAL PART
Esempio 1 - Sintesi di (Z)-5-(5-nitrofuril-2-idene)-1,3-tiazolidin-2,4-dione Example 1 - Synthesis of (Z) -5- (5-nitrofuryl-2-idene) -1,3-thiazolidin-2,4-dione
Tiazolidin-2,4-dione (3 mmol), piperidina (0,03 mmol) e gel di silice attivata (circa 100 mg) vengono mescolati in un vial di vetro 2x12. 5-Nitro-2-furaldeide (3 mmol) viene aggiunta e la miscela risultante viene mescolata a fondo e viene posta in un forno a microonde. Thiazolidin-2,4-dione (3 mmol), piperidine (0.03 mmol) and activated silica gel (approximately 100 mg) are mixed in a 2x12 glass vial. 5-Nitro-2-furaldehyde (3 mmol) is added and the resulting mixture is mixed thoroughly and placed in a microwave oven.
L'irradiazione con le microonde viene effettuata alla potenza di 700 W per 6-8 min. Ogni 60 sec di irradiazione la miscela di reazione viene raffreddata e rimescolata a fondo. Dopo quattro minuti di reazione si aggiungono 0,01 mmoli di acido acetico e la reazione viene portata avanti monitorando ogni 60 sec mediante TLC. The irradiation with microwaves is carried out at the power of 700 W for 6-8 min. Every 60 sec of irradiation the reaction mixture is cooled and thoroughly stirred. After four minutes of reaction, 0.01 mmoles of acetic acid are added and the reaction is carried out by monitoring every 60 sec by TLC.
Al termine della reazione, la miscela, raffreddata a temperatura ambiente, viene cromatografata su colonna di gel di silice, usando acetato di etile come eluente. Dalla fase organica, evaporata sotto vuoto, si ottiene il (Z)-5-(5-nitrofuril-2-idene)-1,3-tiazolidin-2,4-dione come polvere di colore giallo arancio bruno con una resa del 80%. Il punto di fusione à ̈ 224 °C. At the end of the reaction, the mixture, cooled to room temperature, is chromatographed on a silica gel column, using ethyl acetate as eluent. From the organic phase, evaporated under vacuum, (Z) -5- (5-nitrofuryl-2-idene) -1,3-thiazolidin-2,4-dione is obtained as a yellow-orange-brown powder with a yield of 80 %. The melting point is 224 ° C.
Esempio 2 - Sintesi di (Z)-5-(5-nitrofuril-2-idene)-1,3-tiazolidin-2,4-dione Example 2 - Synthesis of (Z) -5- (5-nitrofuryl-2-idene) -1,3-thiazolidin-2,4-dione
Metodo A - 1,17 g (0,01 moli) di tiazolidin-2,4-dione e 1,41 mg (0,01 moli) di 5-nitro-2-furaldeide sono disciolti in benzene (200 ml), si aggiunge piperidina (0,01 mmoli) e la miscela risultante viene messa sotto agitazione e riscaldata a temperatura di riflusso per 8 ore. Si aggiunge quindi alla soluzione di reazione acido acetico (0,01 mmoli) e la reazione viene portata avanti fino alla raccolta della quantità stechiometrica di acqua in una trappola Dean Stark collegata al pallone di reazione. Dopo raffreddamento, dalla soluzione di reazione precipita il prodotto grezzo, che viene lavato con n-esano e cristallizzato da una miscela acetato di etile : n-esano (1:2 v:v). Il prodotto puro si presenta come polvere di colore giallo arancio bruno (resa 77%), con un punto di fusione di 224°C. Method A - 1.17 g (0.01 mol) of thiazolidine-2,4-dione and 1.41 mg (0.01 mol) of 5-nitro-2-furaldehyde are dissolved in benzene (200 ml), yes adds piperidine (0.01 mmol) and the resulting mixture is stirred and heated to reflux temperature for 8 hours. Acetic acid (0.01 mmol) is then added to the reaction solution and the reaction is carried on until the stoichiometric quantity of water is collected in a Dean Stark trap connected to the reaction flask. After cooling, the crude product precipitates from the reaction solution, which is washed with n-hexane and crystallized from a mixture of ethyl acetate: n-hexane (1: 2 v: v). The pure product appears as a yellow-orange brown powder (yield 77%), with a melting point of 224 ° C.
Metodo B - 1,18 g (0,012 mol) di acetato di potassio anidro e 2,34 g (0,02 mol) di tiazolidin-2,4-dione vengono sciolti a 100°C in 15 minuti in 100 ml di acido acetico glaciale. La miscela ottenuta viene quindi portata a 75°C e vengono aggiunti in una sola volta 1,41 g (0,01 mol) di 5-nitro-2-furaldeide sciolti in 150 ml di acido acetico glaciale. La miscela di reazione risultante viene riscaldata a 115°C per 45 minuti. Dopo raffreddamento, la soluzione di reazione viene versata su ghiaccio (200 g) e lasciata tutta la notte a temperatura ambiente. Il precipitato che si forma viene raccolto per filtrazione, lavato con etanolo e seccato. La resa à ̈ di 1,65 g di (Z)-5-(5-nitrofuril-2-idene)-1,3-tiazolidin-2,4-dione (resa 77%) con punto di fusione di 224 °C. Method B - 1.18 g (0.012 mol) of anhydrous potassium acetate and 2.34 g (0.02 mol) of thiazolidine-2,4-dione are dissolved at 100 ° C in 15 minutes in 100 ml of acetic acid glacial. The mixture obtained is then brought to 75 ° C and 1.41 g (0.01 mol) of 5-nitro-2-furaldehyde dissolved in 150 ml of glacial acetic acid are added at one time. The resulting reaction mixture is heated to 115 ° C for 45 minutes. After cooling, the reaction solution is poured on ice (200 g) and left overnight at room temperature. The precipitate that forms is collected by filtration, washed with ethanol and dried. The yield is 1.65 g of (Z) -5- (5-nitrofuryl-2-idene) -1,3-thiazolidin-2,4-dione (yield 77%) with a melting point of 224 ° C .
Dati analitico spettrali del (Z)-5-((5-nitrofuril-2-iden)tiazolidin-2,4-dione:<1>H NMR (CDCl3): Î ́ 6,9 (d, 1H, ArH), Î ́ 7,42 (d, 1H, ArH), Î ́ 7,58 (s, 1H, =CHAr); MS (ESI-): m/z calcd 240, found 239,1. Spectral analytical data of (Z) -5 - ((5-nitrofuryl-2-iden) thiazolidin-2,4-dione: <1> H NMR (CDCl3): Î ́ 6.9 (d, 1H, ArH), Î ́ 7.42 (d, 1H, ArH), Î ́ 7.58 (s, 1H, = CHAr); MS (ESI-): m / z calcd 240, found 239.1.
Esempio 3 - Preparazione del sale potassico di (Z)-5-(5-nitrofuril-2-iden)-1,3-tiazolidin-2,4-dione Example 3 - Preparation of the potassium salt of (Z) -5- (5-nitrofuryl-2-iden) -1,3-thiazolidin-2,4-dione
Per preparare il sale potassico, (Z)-5-(5-nitrofuril-2-iden)-1,3-tiazolidin-2,4-dione (3 mmoli) viene sospeso in etanolo assoluto (10 ml) e trattato a 0°C con una soluzione di 150 mg di KOH (3 mmoli) in etanolo assoluto (5 ml). La miscela di reazione viene posta sotto agitazione per due ore a temperatura ambiente. Il precipitato di sale potassico viene filtrato, lavato con metanolo e seccato (resa 98 %). Il punto di fusione à ̈ di 288 °C. To prepare the potassium salt, (Z) -5- (5-nitrofuryl-2-iden) -1,3-thiazolidin-2,4-dione (3 mmol) is suspended in absolute ethanol (10 ml) and treated at 0 ° C with a solution of 150 mg of KOH (3 mmoles) in absolute ethanol (5 ml). The reaction mixture is stirred for two hours at room temperature. The potassium salt precipitate is filtered, washed with methanol and dried (yield 98%). The melting point is 288 ° C.
Dati analitico spettrali del (Z)-5-((5-nitrofuril-2-iden)-1,3-tiazolidin-2,4-dione sale potassico:<1>H NMR (D2O), chemical shift in Î ́: 6.67 (d, 1H, 3'H, J=10 Hz), 6.96 (s, 1H, H metilene); la parte che le differenzia sta nei sostituenti legati al doppio legame in 5 dell’anello tiazolidindionico. Spectral analytical data of (Z) -5 - ((5-nitrofuril-2-iden) -1,3-thiazolidin-2,4-dione potassium salt: <1> H NMR (D2O), chemical shift in Î ́: 6.67 (d, 1H, 3'H, J = 10 Hz), 6.96 (s, 1H, H methylene); the part that differentiates them lies in the substituents linked to the double bond in 5 of the thiazolidinedionic ring.
VALUTAZIONE DELL’ATTIVITÀ BIOLOGICA EVALUATION OF THE BIOLOGICAL ACTIVITY
Animali Animals
Topi C57BL/6 (8-12 settimane) e Ratti Spontaneamente Ipertesi (RSI) di 6 settimane di età sono stati acquistati da Charles River (Calco, IT). C57BL / 6 mice (8-12 weeks) and 6-week-old Spontaneously Hypertensive Rats (RSI) were purchased from Charles River (Calco, IT).
Misurazione dell’attività di P13K Measurement of P13K activity
Le proteine ricombinanti P13Kγ, P13KÎ ́, P13Kα e P13Kβ sono state incubate con una molecola di formula (I) a varie dosi (1 mM, 200 µM, 40 µM, 8 µM, 1,6 µM, 320 nM, 64 nM e 12,8 nM). L’attività del P13K à ̈ stata valutata aggiungendo una mix di fosfatidilinositolo (1 mg/ml) e fosfatidilserina (1 mg/ml) alla reazione contenente 60 µM di ATP e 5µCi di<32>P-ATP radioattivo, lasciando la reazione a 30°C per 10 minuti. La reazione à ̈ stata poi interrotta aggiungendo una soluzione di CHCl3/MetOH (1:1) e centrifugata. I lipidi sono stati essiccati e risospesi in 30µl e centrifugati. Infine, gocce del campione sono state applicate ad una piastra TLC, poi sviluppata in una tanica di vetro per cromatografia ed esposta ad una lastra radiografica. The recombinant proteins P13Kγ, P13KÎ ́, P13KÎ ± and P13Kβ were incubated with a molecule of formula (I) at various doses (1 mM, 200 µM, 40 µM, 8 µM, 1.6 µM, 320 nM, 64 nM and 12.8 nM). The activity of P13K was evaluated by adding a mix of phosphatidylinositol (1 mg / ml) and phosphatidylserine (1 mg / ml) to the reaction containing 60 µM of ATP and 5µCi of <32> radioactive P-ATP, leaving the reaction at 30 ° C for 10 minutes. The reaction was then stopped by adding a solution of CHCl3 / MetOH (1: 1) and centrifuged. The lipids were dried and resuspended in 30µl and centrifuged. Finally, droplets of the sample were applied to a TLC plate, then developed in a glass tank for chromatography and exposed to an X-ray plate.
Somministrazione del farmaco Administration of the drug
Le molecole di formula (I) sono state disciolte in acqua ed usate a varie dosi, mediante iniezione acuta nella vena giugulare con pompa di infusione. La somministrazione cronica à ̈ stata ottenuta mediante iniezioni i.p. giornaliere, con minipompa osmotica (25 µl/hr per 12 giorni) o con bolo gastrico. The molecules of formula (I) were dissolved in water and used at various doses, by acute injection into the jugular vein with an infusion pump. Chronic administration was achieved by i.p. daily, with osmotic mini-pump (25 µl / hr for 12 days) or with gastric bolus.
Misurazione della pressione sanguigna Blood pressure measurement
Negli esperimenti di trattamento cronico, la pressione sanguigna à ̈ stata valutata in topi svegli mediante radiotelemetria (Data Sciences International. St. Paul, MN, USA) o mediante pletismografia non invasiva sulla coda (Visitech Systems, Apex, NC, USA). Per l’analisi radiotelemetrica, il catetere di misurazione à ̈ stato impiantato nell’arteria femorale e la pressione sanguigna ed il battito cardiaco sono stati registrati giornalmente tra le 9 AM e le 12 AM. In chronic treatment experiments, blood pressure was assessed in awake mice by radiotelemetry (Data Sciences International. St. Paul, MN, USA) or by non-invasive tail plethysmography (Visitech Systems, Apex, NC, USA). For radiotelemetry analysis, the measuring catheter was implanted in the femoral artery and blood pressure and heart rate were recorded daily between 9 AM and 12 AM.
Misurazione del flusso sanguigno Blood flow measurement
Il flusso sanguigno e la resistenza periferica totale (TPR) sono stati misurati mediante catetere Millar ad alta fedeltà . TPR à ̈ stata calcolata dividendo la pressione arteriosa media per il flusso sanguigno. Blood flow and total peripheral resistance (TPR) were measured using a high-fidelity Millar catheter. TPR was calculated by dividing mean arterial pressure by blood flow.
Valutazione della funzionalità vascolare Evaluation of vascular function
Arterie mesenteriche isolate sono state poste in un miografo a pressione e soggette a 100 mmHg di pressione (se non indicato altrimenti); la funzionalità vascolare à ̈ stata quindi misurata. Dove indicato, l’endotelio à ̈ stato rimosso meccanicamente e tale condizione à ̈ stata testata mediante ACh. Isolated mesenteric arteries were placed in a pressure myograph and subjected to 100 mmHg of pressure (unless otherwise indicated); vascular function was then measured. Where indicated, the endothelium was mechanically removed and this condition was tested using ACh.
Analisi statistica Statistic analysis
I dati sono presentati come media ± SEM. Comparazioni multiple sono state valutate mediante ANOVA a 2 vie seguito da test post hoc (GraphPad Prism Software 5, Inc.) Risultati sperimentali Data are presented as mean ± SEM. Multiple comparisons were evaluated by 2-way ANOVA followed by post hoc testing (GraphPad Prism Software 5, Inc.) Experimental results
L’attività delle molecole di formula (I) à ̈ stata testata su vari modelli sperimentali. I dati si mostrati nelle figure riferiscono al composto dell’esempio 3. The activity of the molecules of formula (I) has been tested on various experimental models. The data shown in the figures refer to the compound of example 3.
Innanzitutto, tale molecola à ̈ stata testata per l’efficacia di inibizione delle diverse isoforme di PI3K. First of all, this molecule has been tested for its effectiveness in inhibiting the different isoforms of PI3K.
Come mostrato in tabella (figura 10) la concentrazione EC50 per l’isoforma gamma risultava più bassa di quella necessaria per inibire le altre isoforme. L’attività delle molecole di formula (I) à ̈ stata confrontata con quella della molecola commerciale AS605240. Sono stati valutati gli effetti di un trattamento cronico per i.p. (5 giorni e più) risultando significativi e dose-dipendenti, già dal primo giorno di trattamento. In figura 1 sono riportati gli effetti, ad uno e cinque giorni dalla somministrazione, della dose massima (40 mg*kg<-1>) confrontati con quelli della molecola commerciale AS605240 (40 mg*kg<-1>). As shown in the table (figure 10), the EC50 concentration for the gamma isoform was lower than that necessary to inhibit the other isoforms. The activity of the molecules of formula (I) was compared with that of the commercial molecule AS605240. The effects of chronic treatment for i.p. were evaluated. (5 days and more) resulting significant and dose-dependent, already from the first day of treatment. Figure 1 shows the effects, one and five days after administration, of the maximum dose (40 mg * kg <-1>) compared with those of the commercial molecule AS605240 (40 mg * kg <-1>).
E’ stata quindi testata l’inibizione di P13Kγ mediante trattamento orale giornaliero, che à ̈ normalmente la terapia scelta per il trattamento anti-ipertensivo. In questo caso, gli effetti di abbassamento pressorio dosedipendenti sono diventati significativi 5 giorni dopo l’inizio del trattamento e si sono mantenuti consistenti fino alla fine del trattamento (Figura 2). P13Kγ inhibition was then tested by daily oral treatment, which is normally the therapy of choice for anti-hypertensive treatment. In this case, the dose-dependent blood pressure lowering effects became significant 5 days after the start of treatment and remained consistent until the end of treatment (Figure 2).
Per dimostrare la selettività dell’approccio farmacologico prescelto, topi P13Kγ+/+ e P13Kγ-/- sono stati trattati in modo cronico, per iniezione i.p.. Sia AS605240 che le molecole di formula (I) testate hanno ridotto i livelli di pressione sanguigna nei topi P13Kγ+/+, ma non nei topi P13Kγ-/- (Figure 3A e B). Visto che P13Kγ possiede sia un’attività chinasi-dipendente che una chinasi-indipendente, à ̈ stato valutato l’effetto ipotensivo in topi geneticamente modificati che esprimono un mutante di P13Kγ in cui la chinasi à ̈ inattiva (P13Kγ<kD/kD>): anche in questi topi le molecole testate non hanno esercitato alcuna attività ipotensiva (Figura 4A e B). Questi esperimenti provano che il target molecolare delle molecole di formula (I) à ̈ effettivamente P13Kγ e che il meccanismo à ̈ chinasi-dipendente. To demonstrate the selectivity of the chosen pharmacological approach, P13Kγ + / + and P13Kγ - / - mice were treated chronically, by i.p. injection. Both AS605240 and the molecules of formula (I) tested reduced blood pressure levels. in P13Kγ + / + mice, but not in P13Kγ - / - mice (Figures 3A and B). Since P13Kγ possesses both kinase-dependent and kinase-independent activity, the hypotensive effect was evaluated in genetically modified mice expressing a P13Kγ mutant in which the kinase is inactive (P13Kγ <kD / kD >): even in these mice the tested molecules did not exert any hypotensive activity (Figure 4A and B). These experiments prove that the molecular target of the molecules of formula (I) is actually P13Kγ and that the mechanism is kinase-dependent.
Le molecole di formula (I) sono quindi state testate in modelli di ipertensione nei roditori, mediante varie vie di somministrazione. The molecules of formula (I) were then tested in models of hypertension in rodents, by various routes of administration.
Un trattamento orale giornaliero cronico ha normalizzato i livelli di pressione sanguigna in due modelli murini in cui l’ipertensione era stata indotta mediante infusione cronica di angiotensina II (AngII) (Figure 5A e B) o di L-NAME, un inibitore di ossidonitrico-sintasi (Figure 6A e B). L’analisi à ̈ stata quindi estesa anche su RSI (Ratti Spontaneamente Ipertesi), il migliore modello animale di ipertensione essenziale. Mentre i ratti trattati con il veicolo continuavano ad incrementare i livelli di SBP, il trattamento con le molecole di formula (I) induceva una significativa riduzione di tali livelli pressori e contrastava l’ulteriore aumento pressorio nel tempo (Figura 7). Chronic daily oral treatment normalized blood pressure levels in two mouse models in which hypertension was induced by chronic infusion of angiotensin II (AngII) (Figures 5A and B) or L-NAME, an oxidonitric inhibitor - synthase (Figures 6A and B). The analysis was therefore also extended to RSI (Spontaneously Hypertensive Rats), the best animal model of essential hypertension. While the rats treated with the vehicle continued to increase SBP levels, treatment with the molecules of formula (I) induced a significant reduction in these blood pressure levels and counteracted the further increase in blood pressure over time (Figure 7).
Per comprendere il meccanismo di azione delle molecole dell’invenzione, à ̈ stato misurata la portata cardiaca sanguigna e sono state calcolate le resistenze periferiche totali, prima e dopo somministrazione del farmaco. Come mostrato in Figura 8, le molecole di formula (I) hanno significativamente ridotto le resistenze vascolari, senza modificare il flusso sanguigno (5588±329 contro 5307±215 µl/min). Sulla base di questi risultati, sono stati esplorati gli effetti delle molecole di formula (I) su arterie mesenteriche isolate. To understand the mechanism of action of the molecules of the invention, the cardiac blood output was measured and the total peripheral resistance, before and after drug administration, was calculated. As shown in Figure 8, the molecules of formula (I) significantly reduced vascular resistance, without modifying the blood flow (5588 ± 329 against 5307 ± 215 µl / min). On the basis of these results, the effects of the molecules of formula (I) on isolated mesenteric arteries were explored.
Le molecole dell’invenzione hanno esercitato un aumento dose-dipendente del diametro interno delle arterie mesenteriche perfuse, il che indica un chiaro effetto di vasodilatatore, assente nei topi P13Kγ-/- (Figura 9A). The molecules of the invention exerted a dose-dependent increase in the internal diameter of the perfused mesenteric arteries, indicating a clear vasodilator effect, absent in P13Kγ - / - mice (Figure 9A).
Inoltre, l’effetto vaso rilassante causato dalle molecole di formula (I) non à ̈ stato modificato dalla rimozione dell’endotelio (Figura 9B), il che indica un’azione sulla muscolatura liscia. Furthermore, the vaso-relaxing effect caused by the molecules of formula (I) was not modified by the removal of the endothelium (Figure 9B), which indicates an action on smooth muscle.
I composti dell’invenzione agiscono quindi in modo specifico come inibitori di P13Kγ, costituendo un’efficace terapia dell’ipertensione arteriosa. Il fatto che P13Kγ sia coinvolta anche in altri meccanismi molecolari, in particolare nei processi infiammatori e nei danni a livello cardiaco, rende ancora più promettente la presente terapia dell’ipertensione, rendendo possibile un’azione combinata su vari target farmacologici. The compounds of the invention therefore act specifically as inhibitors of P13Kγ, constituting an effective therapy for arterial hypertension. The fact that P13Kγ is also involved in other molecular mechanisms, in particular in inflammatory processes and damage to the heart, makes the present therapy of hypertension even more promising, making possible a combined action on various pharmacological targets.
Un ulteriore oggetto della presente invenzione à ̈ pertanto costituito dai composti a struttura tiazolidindionica di formula (I) per l’uso nella terapia dell’ipertensione arteriosa. In particolare, tale terapia dell’ipertensione arteriosa comporta la prevenzione di eventi cardiovascolari e cerebrovascolari. A further object of the present invention is therefore constituted by the compounds having a thiazolidinedionic structure of formula (I) for use in the therapy of arterial hypertension. In particular, this treatment of arterial hypertension involves the prevention of cardiovascular and cerebrovascular events.
Secondo la presente invenzione la dose dei composti di formula (I) proposta per la somministrazione ad un uomo (con peso corporeo di circa 70 Kg) va da 1 mg a 1 g e, preferibilmente, da 50 mg a 500 mg del principio attivo per unità di dose. L’unità di dose può essere somministrata, per esempio, da 1 a 4 volte al giorno. La dose dipenderà dalla via prescelta per la somministrazione. Si dovrà considerare che potrebbe essere necessario fare continue variazioni del dosaggio a seconda dell’età e del peso del paziente ad anche della gravità della condizione clinica da trattare. L’esatta dose e la via di somministrazione sarà infine a discrezione del medico curante. According to the present invention, the dose of the compounds of formula (I) proposed for administration to a man (with a body weight of about 70 kg) ranges from 1 mg to 1 g and, preferably, from 50 mg to 500 mg of the active ingredient per unit. of dose. The dose unit can be administered, for example, 1 to 4 times per day. The dose will depend on the chosen route of administration. It should be considered that it may be necessary to make continuous changes in the dosage according to the age and weight of the patient as well as the severity of the clinical condition to be treated. The exact dose and route of administration will ultimately be at the discretion of the treating physician.
Costituisce un ulteriore oggetto dell’invenzione una composizione farmaceutica contenente uno o più molecole di formula (I), unitamente a veicoli ed eccipienti farmaceuticamente accettabili. A further object of the invention is a pharmaceutical composition containing one or more molecules of formula (I), together with pharmaceutically acceptable carriers and excipients.
I composti secondo la presente invenzione possono essere formulati per una somministrazione orale, buccale, parenterale, rettale o transdermica oppure in una forma adatta per la somministrazione per inalazione o insufflazione (sia per bocca che per naso). The compounds according to the present invention can be formulated for oral, buccal, parenteral, rectal or transdermal administration or in a form suitable for administration by inhalation or insufflation (both by mouth and nose).
Per la somministrazione orale, le composizioni farmaceutiche si possono trovare, per esempio, sotto forma di compresse o capsule preparate nel modo convenzionale con gli eccipienti farmaceuticamente accettabili quali agenti leganti (ad esempio amido di mais pregelatinizzato, polivinilpirrolidone o metilcellulosa idrossipropile); agenti di riempimento (ad esempio lattosio, cellulosa microcristallina o idrogeno fosfato di calcio); lubrificanti (ad esempio stearato di magnesio, talco o silice); disintegranti (ad esempio amido di patata o glicolato amido di sodio); o agenti inibenti (ad esempio lauril solfato di sodio). Le compresse possono essere ricoperte con i metodi ben noti nell’arte. Le preparazioni liquide per la somministrazione orale possono presentarsi, per esempio, sotto forme di soluzioni, sciroppi o sospensioni oppure si possono presentare come prodotti liofilizzati da ricostituire, prima dell’uso, con acqua o altri opportuni veicoli. Tali preparazioni liquide possono essere preparate attraverso i metodi convenzionali con gli additivi farmaceuticamente accettabili quali agenti di sospensione (ad esempio sciroppo di sorbitolo, derivati della cellulosa o grassi idrogenati commestibili); agenti emulsionanti (ad esempio lecitina o acacia); veicoli non acquosi (ad esempio olio di mandorle, esteri oleosi, alcool etilico o oli vegetali frazionati); e conservanti (ad esempio metil- o propil-p-idrossibenzoati o acido sorbico). La preparazione può anche opportunamente contenere aromi, coloranti e agenti dolcificanti. For oral administration, the pharmaceutical compositions can be found, for example, in the form of tablets or capsules prepared in the conventional way with pharmaceutically acceptable excipients such as binding agents (e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); filling agents (e.g. lactose, microcrystalline cellulose or calcium hydrogen phosphate); lubricants (e.g. magnesium stearate, talc or silica); disintegrants (for example potato starch or sodium starch glycolate); or inhibiting agents (e.g. sodium lauryl sulfate). The tablets can be coated with the methods well known in the art. Liquid preparations for oral administration can be presented, for example, in the form of solutions, syrups or suspensions or they can be presented as lyophilized products to be reconstituted, before use, with water or other suitable vehicles. Such liquid preparations can be prepared by conventional methods with pharmaceutically acceptable additives such as suspending agents (e.g. sorbitol syrup, cellulose derivatives or edible hydrogenated fats); emulsifying agents (e.g. lecithin or acacia); non-aqueous vehicles (e.g. almond oil, oily esters, ethyl alcohol or fractionated vegetable oils); and preservatives (e.g. methyl- or propyl-p-hydroxybenzoates or sorbic acid). The preparation may also suitably contain flavors, dyes and sweetening agents.
Le preparazioni per la somministrazione orale possono essere formulate in modo opportuno per permettere il rilascio controllato del principio attivo. Preparations for oral administration can be formulated appropriately to allow controlled release of the active ingredient.
Per la somministrazione buccale, le composizioni possono trovarsi sotto forma di compresse o pastiglie formulate nel modo convenzionale, adatte ad un assorbimento a livello della mucosa buccale. Formulazioni buccali tipiche sono le compresse per somministrazione sub-linguale. For buccal administration, the compositions can be in the form of tablets or tablets formulated in the conventional manner, suitable for absorption at the level of the buccal mucosa. Typical buccal formulations are tablets for sublingual administration.
I composti secondo la presente invenzione possono essere formulati per una somministrazione parenterale mediante iniezione. Le formulazioni per le iniezioni possono essere presentate in forma di un’unica dose ad esempio in fiale, con un conservante aggiunto. Le composizioni possono presentarsi sotto tale forma come sospensioni, soluzioni o emulsioni in veicoli oleosi o acquosi e possono contenere agenti del formulario quali agenti di sospensione, stabilizzanti e/o disperdenti. In alternativa, il principio attivo si può trovare sotto forma di polvere per essere ricostituito, prima dell’uso, con un opportuno veicolo, ad esempio con acqua sterile. The compounds according to the present invention can be formulated for parenteral administration by injection. The formulations for injections can be presented in the form of a single dose, for example in ampoules, with an added preservative. The compositions may come in this form as suspensions, solutions or emulsions in oily or aqueous vehicles and may contain formulary agents such as suspending, stabilizing and / or dispersing agents. Alternatively, the active principle can be found in the form of a powder to be reconstituted, before use, with an appropriate vehicle, for example with sterile water.
Secondo la presente invenzione, i composti possono anche essere formulati secondo composizioni rettali quali supposte o clistere da ritenzione, ad esempio contenenti i componenti base delle comuni supposte come burro di cacao o altri gliceridi. According to the present invention, the compounds can also be formulated according to rectal compositions such as suppositories or retention enema, for example containing the basic components of common suppositories such as cocoa butter or other glycerides.
In aggiunta alle composizioni descritte precedentemente, i composti possono anche essere formulati come preparazioni di deposito. Tali formulazioni a lunga azione possono essere somministrate per impianto (ad esempio in modo sottocutaneo, transcutaneo o intramuscolare) o per iniezione intramuscolare. Quindi, per esempio, i composti, secondo la presente invenzione, possono essere formulati con appropriati materiali polimerici o idrofobici (per esempio sotto forma di un’emulsione in un olio adatto) o resine a scambio ionico o come derivati minimamente solubili, per esempio come sale minimamente solubile. In addition to the compositions described above, the compounds can also be formulated as deposit preparations. Such long-acting formulations can be administered by implantation (e.g. subcutaneously, transcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds according to the present invention can be formulated with appropriate polymeric or hydrophobic materials (for example in the form of an emulsion in a suitable oil) or ion exchange resins or as minimally soluble derivatives, for example as a minimally soluble salt.
In generale, le composizioni farmaceutiche dell’invenzione potranno essere preparate secondo metodiche convenzionali, ben note all’esperto del settore, quali quelle descritte in Remington's Pharmaceutical Sciences Handbook, Mack Pub. Co., N.Y., USA, 17th edition, 1985. In general, the pharmaceutical compositions of the invention can be prepared according to conventional methods, well known to the skilled in the art, such as those described in Remington's Pharmaceutical Sciences Handbook, Mack Pub. Co., N.Y., USA, 17th edition, 1985.
Claims (14)
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
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US11926616B2 (en) | 2018-03-08 | 2024-03-12 | Incyte Corporation | Aminopyrazine diol compounds as PI3K-γ inhibitors |
US11046658B2 (en) | 2018-07-02 | 2021-06-29 | Incyte Corporation | Aminopyrazine derivatives as PI3K-γ inhibitors |
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