ITMI20072266A1 - NEW NON-SELECTIVE SOMATOSTATINE ANALOGUES - Google Patents
NEW NON-SELECTIVE SOMATOSTATINE ANALOGUES Download PDFInfo
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- ITMI20072266A1 ITMI20072266A1 ITMI20072266A ITMI20072266A1 IT MI20072266 A1 ITMI20072266 A1 IT MI20072266A1 IT MI20072266 A ITMI20072266 A IT MI20072266A IT MI20072266 A1 ITMI20072266 A1 IT MI20072266A1
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Description
DESCRIZIONE DESCRIPTION
La presente invenzione è relativa a nuovi ciclopeptidi analoghi funzionali non selettivi della somatostatina, ai loro coniugati e complessi, ai processi per la loro produzione, alle formulazioni che li contengono e ai loro usi in campo farmaceutico. The present invention relates to new non-selective functional analogue cyclopeptides of somatostatin, their conjugates and complexes, the processes for their production, the formulations containing them and their uses in the pharmaceutical field.
STATO DELL’ARTE STATE OF THE ART
Peptidi ciclici agonisti di somatostatina sono noti da tempo [J Pept Res 58 (2), 91 (2001)]: in particolare due di questi, octreotide e lanreotide, sono utilizzati in clinica per la cura dell’acromegalia e per il trattamento sintomatico di carcinomi. Cyclic agonist peptides of somatostatin have been known for some time [J Pept Res 58 (2), 91 (2001)]: in particular two of these, octreotide and lanreotide, are used in the clinic for the treatment of acromegaly and for the symptomatic treatment of carcinomas.
La somatostatina agisce attraverso l’interazione con 5 sottotipi di recettori (SSTR1, 2, 3, 4 e 5); ma gli analoghi sinora impiegati in terapia, sono tuttavia essenzialmente selettivi per il solo recettore SSTR2. Somatostatin acts through interaction with 5 subtypes of receptors (SSTR1, 2, 3, 4 and 5); but the analogues used up to now in therapy are nevertheless essentially selective for the SSTR2 receptor alone.
La grande maggioranza degli agonisti già noti è caratterizzata dalla presenza, nella struttura peptidica, del frammento -DTrp-Lys-; questo frammento, sembra quindi essenziale per l’attività degli analoghi ed è infatti presente anche in octreotide e lanreotide. The great majority of known agonists are characterized by the presence, in the peptide structure, of the fragment -DTrp-Lys-; this fragment therefore seems essential for the activity of the analogs and is in fact also present in octreotide and lanreotide.
Recentemente è stata avanzata l’ipotesi che analoghi meno selettivi, in grado cioè di interagire anche con gli altri sottotipi recettoriali, possano offrire un vantaggio dal punto di vista dell’uso terapeutico [Nature Rev. Drug Discovery 2, 999 (2003)]. The hypothesis has recently been advanced that less selective analogues, that is, capable of interacting with other receptor subtypes, may offer an advantage from the point of view of therapeutic use [Nature Rev. Drug Discovery 2, 999 (2003)].
Nella domanda di brevetto W02002010192 è stato descritto un ciclopeptide che risulta molto affine per il recettore SSTR5, presenta una minore affinità per SSTR2 ed SSTR3 e un’affinità quasi nulla per SSTR4. Per SSTR1 viene descritta un’affinità circa 60 volte inferiore a quella per SSTR5. Patent application W02002010192 describes a cyclopeptide which is very similar to the SSTR5 receptor, has a lower affinity for SSTR2 and SSTR3 and almost zero affinity for SSTR4. An affinity about 60 times lower than that for SSTR5 is described for SSTR1.
Gli stessi inventori di W02002010192, in una pubblicazione successiva [Nature Rev. Drug Discovery 2, 999 (2003)], sostengono l’importanza dei recettori SSTR1, 2 e 5 per l’attività antisecretoria di somatostatina, ma riportano, per lo stesso ciclopeptide descritto nella suddetta domanda di brevetto, un’affinità per SSTR1 di circa 300 volte inferiore a quella per SSTR5. The same inventors of W02002010192, in a subsequent publication [Nature Rev. Drug Discovery 2, 999 (2003)], argue the importance of SSTR1, 2 and 5 receptors for the antisecretory activity of somatostatin, but report, for the same cyclopeptide described in the aforementioned patent application, an affinity for SSTR1 about 300 times lower than that for SSTR5.
E’ chiaro che, in questo caso, una possibile attività terapeutica mediata dalla interazione con il recettore SSTR1 potrà realizzarsi solo in presenza di un notevole sovradosaggio rispetto alle azioni mediate dall’interazione con SSTR5. It is clear that, in this case, a possible therapeutic activity mediated by the interaction with the SSTR1 receptor will be realized only in the presence of a significant overdose compared to the actions mediated by the interaction with SSTR5.
Quindi, mentre non è chiaro il possibile ruolo terapeutico di agonisti per il recettore SSTR4, appare evidente la necessità, e la possibile utilità, di nuovi analoghi di somatostatina con un livello di affinità paragonabile per tutti gli altri quattro recettori. Thus, while the possible therapeutic role of SSTR4 receptor agonists is unclear, the need, and the possible usefulness, of novel somatostatin analogs with a comparable level of affinity for all the other four receptors appears evident.
In particolare, i potenziali vantaggi terapeutici di agonisti in grado di interagire con SSTR1 sono riportati nella letteratura: M.C. Zatelli e coll, hanno studiato, in vitro, l’effetto di agonisti per SSTR1 su adenomi pituitari umani, sia secernenti [J Clin End&Met 88, 2797 (2003)], che clinicamente non-funzionali [J Clin End&Met 89, 5181 (2004)]; in ambedue i casi lo stimolo di recettori SSTR1 ha portato ad una riduzione dell’attività secretoria e della vitalità cellulare. D’altra parte, il potenziale vantaggio terapeutico che può derivare dall’uso di analoghi pluripotenti di somatostatina (in grado di interagire con i recettori SSTR1, 2, 3 e 5) è stato anche evidenziato da J. van der Hoek e coll. In una recente rassegna [Curr. Pharm. Design 11, 1573 (2005)]; è infatti messo in evidenza come diversi tumori, sia pituitari, che gastroenteropancreatici (GEP), esprimano, sulla superficie cellulare, percentuali variabili ma significative di tutti e quattro i recettori, mentre il recettore SSTR4 risulta molto meno presente. In particular, the potential therapeutic advantages of agonists capable of interacting with SSTR1 are reported in the literature: M.C. Zatelli et al, studied, in vitro, the effect of SSTR1 agonists on human pituitary adenomas, both secreting [J Clin End & Met 88, 2797 (2003)], and clinically non-functional [J Clin End & Met 89, 5181 (2004 )]; in both cases, the stimulation of SSTR1 receptors led to a reduction in secretory activity and cell viability. On the other hand, the potential therapeutic advantage that can derive from the use of pluripotent analogues of somatostatin (capable of interacting with the SSTR1, 2, 3 and 5 receptors) was also highlighted by J. van der Hoek and coll. In a recent review [Curr. Pharm. Design 11, 1573 (2005)]; it is in fact highlighted how different tumors, both pituitary and gastroenteropancreatic (GEP), express variable but significant percentages of all four receptors on the cell surface, while the SSTR4 receptor is much less present.
La domanda W020050 14624 descrive la preparazione di analoghi ciclici della somatostatina e gli intermedi usati nella loro preparazione. Questi analoghi esaciclici presentano il residuo triptofanico in posizione 3. Application WO20050 14624 describes the preparation of cyclic analogs of somatostatin and the intermediates used in their preparation. These hexacyclic analogs have the tryptophan residue in position 3.
La domanda W02006066868 descrive composizioni farmaceutiche per la somministrazione parenterale di alcuni sali di analoghi della somatostatina, che formano un gel di deposito dopo Tiniezione a contatto con i fluidi corporei. Per analoghi della somatostatina si intendono i peptidi lineari o ciclici derivati dalla somatostatina, che comprendono una sequenza di aminoacidi comprendenti triptofano. Application WO2006066868 describes pharmaceutical compositions for the parenteral administration of some salts of somatostatin analogues, which form a storage gel after injection in contact with body fluids. By somatostatin analogues we mean linear or cyclic peptides derived from somatostatin, which comprise a sequence of amino acids comprising tryptophan.
In Regulatory Peptides, 1 (1980) 97-113, si sostiene Timportanza del gruppo NH indolico per fattività della somatostatina: la sostituzione di Trp<8>con naftilalanine determina infatti la perdita di attività. In Regulatory Peptides, 1 (1980) 97-113, the importance of the indole NH group is argued for the effectiveness of somatostatin: the substitution of Trp <8> with naphthylalanine in fact determines the loss of activity.
Nell’ articolo non sono riportati dati di binding, mentre è valutata l’attività di inibizione della secrezione gastrica in vivo. I risultati indicano che, per l’attività gastrica, la sostituzione del Trp<8>con analoghi alogenati, metilati o metossilati (tabella Π) ha poca influenza sulla potenza biologica, potenza che è invece quasi azzerata negli analoghi contenenti pentametilfenilalanina (Pmp) oppure naftilalanina (tabella ΠΙ), anziché triptofano. I derivati alogenati del D-Trp sembrano, invece, migliorare notevolmente l’attività di inibizione della secrezione del GH (tabella V). Ricercatori della Merck S&D (vedi Veber D.F. in Proceedings of thel2th Am. Pep. Symp.; Smith, J.A. & Rivier J.E. editors, ESCOM 1992, pp 3-14) riportano che, in esapeptidi ciclici, la sostituzione del triptofano con altri amminoacidi aromatici comporta una notevole perdita di attività, in vitro, nelTinibizione della secrezione di GH. The article does not report binding data, while the activity of inhibition of gastric secretion in vivo is evaluated. The results indicate that, for gastric activity, the substitution of Trp <8> with halogenated, methylated or methoxylated analogues (table Π) has little influence on the biological potency, a potency which is instead almost zero in the analogues containing pentamethylphenylalanine (Pmp) or naphthylalanine (table ΠΙ), instead of tryptophan. The halogenated derivatives of D-Trp seem, on the other hand, to significantly improve the inhibition activity of GH secretion (table V). Merck S&D researchers (see Veber D.F. in Proceedings of thel2th Am. Pep. Symp .; Smith, J.A. & Rivier J.E. editors, ESCOM 1992, pp 3-14) report that, in cyclic hexapeptides, the substitution of tryptophan with other aromatic amino acids involves a considerable loss of activity, in vitro, in the inhibition of GH secretion.
In J Med Chem (2005) 48, 507, sono descritti analoghi selettivi per SSTR1 ed il loro possibile ruolo terapeutico di agonisti. Anche le strutture qui analizzate, presentano il triptofano. In J Med Chem (2005) 48, 507, selective analogues for SSTR1 and their possible therapeutic role as agonists are described. The structures analyzed here also present tryptophan.
L’articolo descrive due serie di analoghi derivati da due ciclopeptidi: uno contenente il D-Trp e l’altro la D-Nal; tutti gli analoghi, come i capostipiti, hanno affinità solo per SSTR1; la serie con D-Nal risulta circa 10 volte meno potente di quella con D-Trp. Particolare di questi peptidi, che sono inattivi su tutti gli altri sottotipi di recettori, è la sostituzione della lisina con p-ammino-fenilalanina. The article describes two series of analogues derived from two cyclopeptides: one containing D-Trp and the other D-Nal; all analogues, like the progenitors, have affinity only for SSTR1; the series with D-Nal is about 10 times less powerful than that with D-Trp. Particular of these peptides, which are inactive on all other receptor subtypes, is the substitution of lysine with p-amino-phenylalanine.
Da quanto sopra esposto risulta perciò evidente che un agonista pluripotente di somatostatina, in grado cioè di stimolare SST1, SSTR2, SSTR3 e SSTR5, aumenterà la possibilità di risposte positive in pazienti affetti da tumori neuroendocrini rispetto ad agonisti in cui la funzione attivatoria è ristretta ad un numero inferiore di sottorecettori della somatostatina. From the above it is therefore evident that a pluripotent agonist of somatostatin, that is able to stimulate SST1, SSTR2, SSTR3 and SSTR5, will increase the possibility of positive responses in patients with neuroendocrine tumors compared to agonists in which the activating function is restricted to fewer somatostatin sub-receptors.
DESCRIZIONE DELL’INVENZIONE DESCRIPTION OF THE INVENTION
La richiedente ha sorprendentemente trovato che il residuo di triptofano, presente in molti analoghi noti, può essere utilmente sostituito con altri opportuni residui aromatici, mantenendo l’affinità per gran parte dei recettori di somatostatina. The Applicant has surprisingly found that the tryptophan residue, present in many known analogues, can be usefully replaced with other suitable aromatic residues, maintaining the affinity for most of the somatostatin receptors.
In particolare è stato trovato che, usando amminoacidi il cui gruppo aromatico sia sufficientemente ricco di elettroni (essendo, per esempio, sostituito con gruppi elettron-donatori) in sostituzione del residuo di triptofano, si ottengono peptidi che mostrano una buona affinità per il recettore SSTR1, a valori di concentrazione simili a quelli necessari per il legame ai recettori SSTR2, SSTR3 e SSTR5. In particular it has been found that, by using amino acids whose aromatic group is sufficiently rich in electrons (being, for example, replaced with electron-donor groups) in place of the tryptophan residue, peptides are obtained which show a good affinity for the SSTR1 receptor. , at concentration values similar to those required for binding to SSTR2, SSTR3 and SSTR5 receptors.
Formano quindi oggetto della presente invenzione dei cicloesapeptidi analoghi di somatostatina, aventi formula (I), dove per cicloesapeptidi analoghi di somatostatina si intendono peptidi con sei residui alfaamminoacidici, nei quali sia presente un legame peptidico diretto tra il gruppo alfa-carbossilico del sesto residuo ed il gruppo alfa-amminico del primo residuo, con affinità di legame a concentrazioni nanomolari, per almeno uno dei recettori noti per somatostatina: Therefore, the object of the present invention are cyclohexapeptides analogues of somatostatin, having formula (I), where by cyclohexapeptides analogues of somatostatin we mean peptides with six alpha-amino acid residues, in which there is a direct peptide bond between the alpha-carboxylic group of the sixth residue and the alpha-amino group of the first residue, with binding affinity at nanomolar concentrations, for at least one of the known receptors for somatostatin:
Formula (I) Formula (I)
dove: where is it:
m = 0, 1 o 2 ed n = l, 2 o 3; preferenzialmente m è uguale a 1 ed n è uguale a 1 o 2; ancora più preferibilmente n è uguale a 1. m = 0, 1 or 2 and n = 1, 2 or 3; preferentially m is equal to 1 and n is equal to 1 or 2; even more preferably n is equal to 1.
RI rappresenta un gruppo aromatico, ad esclusione delTindolo, che preferibilmente è fenile, naftile, benzidrile, fluorenile, stirenile, antranile o bifenile, opzionalmente sostituito in una o più posizioni. I gruppi sostituenti preferiti sono quelli elettron-donatori quali alchile, alchilossile, idrossile, alchilammino, acilammino, solfuro o alchilsolfuro. R1 represents an aromatic group, excluding indole, which is preferably phenyl, naphthyl, benzhydryl, fluorenyl, styrenyl, anthranyl or biphenyl, optionally substituted in one or more positions. The preferred substituent groups are electron-donor groups such as alkyl, alkyloxy, hydroxyl, alkylamino, acylamino, sulphide or alkylsulfide.
Il gruppo RI è preferibilmente gruppo naftalenico, sostituito con uno o più gruppi metilossi, preferibilmente con due gruppi metilossi; in un aspetto ancor più preferito dell’ invenzione, RI è 3,8-dimetossi-naftalen-2-ile. The R1 group is preferably naphthalene group, substituted with one or more metyloxy groups, preferably with two metyloxy groups; in an even more preferred aspect of the invention, RI is 3,8-dimethoxy-naphthalene-2-yl.
R4 rappresenta un gruppo aromatico, eventualmente sostituito. Il gruppo R4 è preferibilmente un gruppo fenile, eventualmente sostituito con un gruppo idrossile, C1-C4alcossile, C1-C4alchile, alogeno o nitro. R4 represents an aromatic group, possibly substituted. The R4 group is preferably a phenyl group, optionally substituted with a hydroxyl, C1-C4alkoxyl, C1-C4alkyl, halogen or nitro group.
R2 ed R3 sono, indipendentemente, H o un gruppo alchilico C1-C4, oppure, unitamente, rappresentano una catena alchilenica C4-C5, legata all’atomo di azoto per formare una struttura ciclica. R2 and R3 are, independently, H or a C1-C4 alkyl group, or, together, they represent a C4-C5 alkylene chain, linked to the nitrogen atom to form a cyclic structure.
Alternativamente R3 può essere un gruppo chelante di cationi o metalli, unito al gruppo amminico direttamente oppure attraverso uno spaziatore. L’eventuale spaziatore può essere uno di quelli già noti nell’arte, per esempio quelli descritti in GB-A-2,225,579 oppure in WO9701579, qui incorporati per riferimento; esso può, per esempio, essere un gruppo di formula -Z-R5-CO-, dove R5 è Ci-n alchilene, Cm alchenilene oppure -CH(R6)-, dove R6 è la catena laterale di un alfa ammino acido, e Z è una funzione capace di formare un legame covalente con il gruppo chelante; Z può per esempio essere un gruppo funzionale capace di formare un legame etereo, estereo o ammidico con un altro gruppo funzionale del gruppo chelante (ad esempio ossidrile, carbossile oppure ammina). Z preferibilmente è un atomo di ossigeno, un atomo di zolfo, un radicale carbonilico (ovvero CO) oppure un radicale amminico (ovvero NH). Alternatively R3 can be a chelating group of cations or metals, joined to the amino group directly or through a spacer. The possible spacer can be one of those already known in the art, for example those described in GB-A-2,225,579 or in WO9701579, incorporated herein by reference; it can, for example, be a group of formula -Z-R5-CO-, where R5 is Ci-n alkylene, Cm alkenylene or -CH (R6) -, where R6 is the side chain of an alpha amino acid, and Z is a function capable of forming a covalent bond with the chelating group; Z may for example be a functional group capable of forming an ether, ester or amide bond with another functional group of the chelating group (for example hydroxyl, carboxyl or amine). Z is preferably an oxygen atom, a sulfur atom, a carbonyl radical (i.e. CO) or an amino radical (i.e. NH).
Il gruppo Z è ancora più preferibilmente un radicale amminico ed il gruppo di formula -Z-R5-CO- sarà un residuo divalente derivante da un acido ammino-carbossilico quali, per esempio, la beta-Alanina (ovvero -NH-(CH2)2-CO-), l’acido 6-amminoesanoico (ovvero -NH-(CH2)5-CO-) o altri. Il gruppo chelante è un gruppo fisiologicamente accettabile, capace di complessare ioni o altri elementi rilevabili o utili per la radioterapia antitumorale ed ha, preferenzialmente, un carattere idrofilico. The Z group is even more preferably an amino radical and the group of formula -Z-R5-CO- will be a divalent residue deriving from an amino-carboxylic acid such as, for example, beta-Alanine (i.e. -NH- (CH2) 2-CO-), 6-aminohexanoic acid (i.e. -NH- (CH2) 5-CO-) or others. The chelating group is a physiologically acceptable group, capable of complexing ions or other detectable or useful elements for anticancer radiotherapy and preferentially has a hydrophilic character.
I gruppi chelanti e gli ioni o altri elementi complessati, possono essere utilmente scelti tra quelli già noti e descritti, per esempio, da Okarvi S.M. in Med. Res. Rev. 24 (3), 357 (2004), da Weiner R.E. e Thakur M.L. BioDrugs 19(3), 145 (2005) oppure in W02002010192, qui incorporati per riferimento. The chelating groups and the ions or other complexed elements can be usefully selected from those already known and described, for example, by Okarvi S.M. in Med. Res. Rev. 24 (3), 357 (2004), by Weiner R.E. and Thakur M.L. BioDrugs 19 (3), 145 (2005) or in WO2002010192, incorporated herein by reference.
II gruppo chelante può essere in forma libera, salificato oppure complessato con ioni o altri elementi, rilevabili per radioattività (radionuclidi) o con altri mezzi oppure utilizzabili per scopi radioterapeutici. The chelating group can be in free form, salified or complexed with ions or other elements, detectable by radioactivity (radionuclides) or by other means or usable for radiotherapeutic purposes.
Preferenzialmente il gruppo chelante sarà derivato dall’acido 1,4,7,10-tetraazaciclododecano-N,N’,N”,N”’-tetraacetico (DOTA) o dall’acido dietilen-triammino-pentaacetico (DTPA) e lo ione sarà uno ione paramagnetico (Gd3+, Fe3+, o altri), fluorescente (Eu3+) o un radionuclide emittente radiazioni α, β o y (11 lln, 99mTc, 169Yb, 177Lu, 90Y, 213Bi o altri). Preferably the chelating group will be derived from 1,4,7,10-tetraazacyclododecane-N, N ', N ", N"' - tetraacetic acid (DOTA) or from diethylene-triamino-pentaacetic acid (DTPA) and the ion it will be a paramagnetic ion (Gd3 +, Fe3 +, or others), fluorescent (Eu3 +) or a radionuclide emitting α, β or y radiation (11 lln, 99mTc, 169Yb, 177Lu, 90Y, 213Bi or others).
XI è un residuo amminoacilico di formula (a), (b) o (c) XI is an aminoacyl residue of formula (a), (b) or (c)
(a) (to)
(b) (b)
(c) (c)
XI è preferibilmente un residuo amminoacilico di formula (c). XI is preferably an aminoacyl residue of formula (c).
I residui amminoacilici, presenti nei cicloesapeptidi di formula (I), possono avere configurazione L o D; preferibilmente i residui 1, 2, e 4-6 sono L, ed il residuo 3 è preferibilmente D. The aminoacyl residues, present in the cyclohexapeptides of formula (I), can have L or D configuration; preferably the residues 1, 2, and 4-6 are L, and the residue 3 is preferably D.
I cicloesapeptidi di formula (I), possono esistere in forma di base libera o come sali. I sali includono quelli di addizione con acidi organici (per esempio acetati, lattati, benzoati, aspartati, pamoati, ecc.), acidi polimerici (per esempio acido polimetacrilico, polistirensulfonico, ecc.) o acidi inorganici (per esempio cloridrati, solfati, nitrati, ecc). The cyclohexapeptides of formula (I) can exist in free base form or as salts. Salts include addition salts with organic acids (e.g. acetates, lactates, benzoates, aspartates, pamoates, etc.), polymeric acids (e.g. polymethacrylic acid, polystyrenesulfonic acid, etc.) or inorganic acids (e.g. hydrochlorides, sulfates, nitrates , etc).
I composti dell’ invenzione sono, in vivo, molto più resistenti ai meccanismi di degradazione in confronto con i ciclodisolfuri analoghi di somatostatina (octreotide, lanreotide, ecc.) ed hanno, conseguentemente, una durata di azione molto più lunga. In alcuni casi, la stabilità e la durata di azione The compounds of the invention are, in vivo, much more resistant to degradation mechanisms in comparison with the analogous cyclodisulfides of somatostatin (octreotide, lanreotide, etc.) and consequently have a much longer duration of action. In some cases, the stability and duration of action
risultano migliori anche rispetto ad altri ciclopeptidi tra quelli già noti per essere agoni sti stabili di somatostatina. they are also better than other cyclopeptides among those already known to be stable somatostatin agons.
La presente invenzione include anche i processi per la produzione dei composti di formula (I), da qui in poi chiamati composti dell’invenzione. I composti dell’invenzione possono essere prodotti utilizzando diverse metodologie sintetiche, per analogia con metodi già noti per altri peptidi. a) Un corrispondente esapeptide lineare, parzialmente protetto, può essere prodotto mediante sintesi in fase solida, in modo tale da lasciare liberi, sia il gruppo alfa-ammino N-terminale, che quello alfa-carbossilico C-terminale; i due gruppi liberi saranno poi fatti reagire, in soluzione, mediante opportuni agenti condensanti e le protezione delle catene laterali saranno infine rimosse, ottenendo il cicloesapeptide desiderato. The present invention also includes the processes for the production of the compounds of formula (I), hereinafter referred to as compounds of the invention. The compounds of the invention can be produced using different synthetic methods, by analogy with methods already known for other peptides. a) A corresponding partially protected linear hexapeptide can be produced by solid phase synthesis, in such a way as to leave both the N-terminal alpha-amino group and the C-terminal alpha-carboxylic group free; the two free groups will then be reacted in solution by means of suitable condensing agents and the side chain protections will finally be removed, obtaining the desired cyclohexapeptide.
b) Alternativamente, la sintesi in fase solida può essere condotta ancorando il peptide alla resina tramite la catena laterale della lisina; in questo caso, dopo aver rimosso selettivamente le protezioni dai gruppi N-terminale e C-terminale, la ciclizzazione può essere condotta ancora in fase solida ed i composti dell’invenzione possono essere ottenuti con un singolo trattamento di deprotezione e distacco dalla resina. b) Alternatively, the solid phase synthesis can be carried out by anchoring the peptide to the resin via the lysine side chain; in this case, after selectively removing the protections from the N-terminal and C-terminal groups, the cyclization can still be carried out in the solid phase and the compounds of the invention can be obtained with a single deprotection and detachment treatment from the resin.
c) In un’altra alternativa, il peptide lineare protetto può essere preparato mediante sintesi in soluzione e poi, dopo aver rimosso selettivamente le protezioni dai gruppi N-terminale e C-terminale, si può procedere come descritto in a). c) In another alternative, the protected linear peptide can be prepared by synthesis in solution and then, after selectively removing the protections from the N-terminal and C-terminal groups, one can proceed as described in a).
II peptide lineare da ciclizzare può essere scelto tra i sei peptidi ipoteticamente ottenibili mediante l’apertura di uno qualunque dei sei legami peptidici presenti nei composti dell’invenzione. La scelta sarà guidata da considerazioni di convenienza sintetica, note agli esperti di sintesi peptidica, ma non influenzerà minimamente la natura del prodotto finale, che sarà comunque identica, qualunque sia la sequenza del peptide lineare scelto; preferenzialmente si sceglieranno peptidi nei quali Γ amminoacido C-terminale è la lisina. The linear peptide to be cyclized can be selected from the six peptides hypothetically obtainable by opening any of the six peptide bonds present in the compounds of the invention. The choice will be guided by considerations of synthetic convenience, known to peptide synthesis experts, but will not in the least influence the nature of the final product, which will in any case be identical, whatever the sequence of the linear peptide chosen; preferably peptides will be chosen in which the C-terminal amino acid is lysine.
Molti dei derivati amminoacidici, necessari per la sintesi dei peptidi, sono noti e disponibili commercialmente. Many of the amino acid derivatives, necessary for the synthesis of the peptides, are known and commercially available.
I derivati della idrossiprolina possono essere preparati come descritto in WO9701579, qui incorporato per riferimento, o con altre procedure simili; alternativamente, i peptidi lineari parzialmente protetti, possono contenere un residuo di idrossiprolina non modificata, e l’introduzione della catena laterale può essere effettuata direttamente sui peptidi lineari, prima della deprotezione, oppure dopo la ciclizzazione, prima della deprotezione finale. Per i derivati chelanti dei composti dell’invenzione, il gruppo protettore della catena legata alla idrossiprolina potrà essere opportunamente scelto in modo tale che sia possibile rimuoverlo selettivamente, lasciando inalterata la protezione della catena laterale della lisina; in questo modo sarà possibile legare il gruppo chelante al gruppo amminico libero, direttamente o tramite uno spaziatore, prima della deprotezione finale. The hydroxyproline derivatives can be prepared as described in WO9701579, incorporated herein by reference, or by other similar procedures; alternatively, the partially protected linear peptides may contain an unmodified hydroxyproline residue, and the introduction of the side chain can be carried out directly on the linear peptides, before deprotection, or after cyclization, before the final deprotection. For the chelating derivatives of the compounds of the invention, the protecting group of the chain linked to hydroxyproline can be suitably chosen in such a way that it can be selectively removed, leaving the protection of the lysine side chain unaltered; in this way it will be possible to bind the chelating group to the free amino group, directly or through a spacer, before the final deprotection.
Alcuni amminoacidi utilizzati nella posizione 3 della formula generale (I), così come i loro derivati, sono nuovi e formano un ulteriore aspetto della presente invenzione. In particolare ci riferiamo agli aminoacidi: Some amino acids used in position 3 of the general formula (I), as well as their derivatives, are new and form a further aspect of the present invention. In particular we refer to amino acids:
3-(3,8-dimetossi-naftalen-2-il)-alanina, 3- (3,8-dimethoxy-naphthalen-2-yl) -alanine,
3-(l,4-dimetossi-naftalen-2-il)-alanina e 3- (1,4-dimethoxy-naphthalen-2-yl) -alanine e
2,5-dimetossi-/homofenilalanina 2,5-dimethoxy- / homophenylalanine
ed ai loro derivati totalmente o parzialmente protetti, corrispondenti alle and their totally or partially protected derivatives, corresponding to
formule (e), (f) e (g): formulas (e), (f) and (g):
3-(3,8-dimetossi-nafìtalen-2-il)-alanina 3- (3,8-dimethoxy-naphthalen-2-yl) -alanine
e derivati and derivatives
3-(l,4-dimetossi-naftalen-2-il)-alanina 3- (1,4-dimethoxy-naphthalen-2-yl) -alanine
e derivati and derivatives
2,5-dimetossi-homofenilalanina 2,5-dimethoxy-homophenylalanine
e derivati and derivatives
Nelle formule (e), (g) ed (f), G può essere un atomo di idrogeno oppure un gruppo protettivo scelto tra quelli noti agli esperti delTarte, p.e. fluoren-9-il-metilossi-carbonile, ter-Butilossi-carbonile o benzilossi-carbonile; W può essere un gruppo ossidrile oppure un gruppo protettivo scelto tra quelli noti agli esperti delTarte, p.e. metilossi, ter-butilossi o benzilossi. Per derivati parzialmente protetti si intendono quei derivati dove solo uno, tra G e W, rappresenta un gruppo protettivo. In formulas (e), (g) and (f), G can be a hydrogen atom or a protective group selected from those known to those skilled in the art, e.g. fluoren-9-yl-methyloxy-carbonyl, tert-butyloxy-carbonyl or benzyloxy-carbonyl; W can be a hydroxyl group or a protective group selected from those known to those skilled in the art, e.g. metyloxy, tert-butyloxy or benzyloxy. Partially protected derivatives are those derivatives where only one, between G and W, represents a protective group.
Essi possono essere preparati adattando metodi già noti in letteratura (vedi per esempio [J Org Chem 55, 2913 (1990)], [Org. Leti. 2, 1089 (2000) e [Synthesis (1983), 38]); per esempio, partendo dall’aldeide corrispondente alla catena laterale desiderata, può essere usato il metodo descritto nello schema 1. They can be prepared by adapting methods already known in the literature (see for example [J Org Chem 55, 2913 (1990)], [Org. Leti. 2, 1089 (2000) and [Synthesis (1983), 38]); for example, starting from the aldehyde corresponding to the desired side chain, the method described in diagram 1 can be used.
SCHEMA 1 DIAGRAM 1
I suddetti derivati possono essere preparati come miscele enantiomeriche raceme (D/L) oppure, mediante sintesi stereoselettive o metodi di risoluzione chirale, possono essere ottenuti come singoli enantiomeri D o L. Tra i metodi di risoluzione chirale possono essere usati metodi di deracemizzazione enzimatica (come, per esempio, quello descritto in US2001021519, qui incorporato per riferimento), nei quali la stereoselettività dell’ enzima (p.e., L o D amminoacido-ossidasi) consente di indurre la racemizzazione di uno solo dei due enantiomeri, dopo di che, ripetuti cicli di trattamento, permettono di raggiungere purezze enantiomeriche elevate. The above derivatives can be prepared as racemic (D / L) enantiomeric mixtures or, by stereoselective synthesis or chiral resolution methods, they can be obtained as single D or L enantiomers. Among the chiral resolution methods, enzymatic deracemization methods can be used ( such as, for example, the one described in US2001021519, incorporated herein by reference), in which the stereoselectivity of the enzyme (e.g., L or D amino acid oxidase) allows to induce the racemization of only one of the two enantiomers, after which, repeated treatment cycles, allow to reach high enantiomeric purities.
Formano anche oggetto della presente invenzione le formulazioni farmaceutiche che contengono i composti dell'invenzione. Pharmaceutical formulations containing the compounds of the invention also form an object of the present invention.
I composti dell’invenzione possono essere somministrati in forma libera o in forma di sali farmaceuticamente accettabili o come complessi. Tali sali e complessi possono essere preparati in modo convenzionale e mostrano lo stesso ordine di attività dei composti liberi. La presente invenzione fornisce inoltre composizioni farmaceutiche comprendenti i composti di formula (I) in forma di base libera o in forma di sali farmaceuticamente accettabili o sotto forma di complessi, insieme ad uno o più eccipienti o diluenti farmaceuticamente accettabili. Tali composizioni possono essere formulate in modo convenzionale. I composti dell’invenzione possono essere somministrati anche in forma di rilascio modificato, per esempio come impianti, microcapsule, microsfere o nanosfere comprendenti, per esempio, polimeri biodegradabili o copolimeri, in forma di formulazioni liposomiali 0 in forma di un autogel, ad esempio composizioni solide o semisolide in grado di formare un gel dopo interazione con i fluidi del corpo del paziente. The compounds of the invention can be administered in free form or in the form of pharmaceutically acceptable salts or as complexes. Such salts and complexes can be prepared in a conventional way and show the same order of activity as the free compounds. The present invention also provides pharmaceutical compositions comprising the compounds of formula (I) in free base form or in the form of pharmaceutically acceptable salts or in the form of complexes, together with one or more pharmaceutically acceptable excipients or diluents. Such compositions can be formulated in a conventional way. The compounds of the invention can also be administered in modified release form, for example as implants, microcapsules, microspheres or nanospheres comprising, for example, biodegradable polymers or copolymers, in the form of liposomal formulations or in the form of an autogel, for example compositions solid or semi-solid capable of forming a gel after interaction with the patient's body fluids.
1 composti dell’invenzione o i loro sali o complessi farmaceuticamente accettabili, possono essere somministrati tramite ogni via convenzionale, per esempio per via parenterale, sotto forma di soluzione o sospensione iniettabile (includendo anche le forme a rilascio modificato sopra indicate), per via orale, usando un promotore d’assorbimento convenzionale, per via nasale o come suppositori o topicamente, per esempio in forma di liquido oftalmico, di gel, di preparazione come unguento o come sospensione, per esempio liposomiale, come formulazione in microsfere o nanosfere, per esempio per instillazione o iniezione sottocongiuntivale oppure intra o peri oculare. The compounds of the invention or their pharmaceutically acceptable salts or complexes can be administered by any conventional route, for example parenterally, in the form of solution or suspension for injection (also including the modified release forms indicated above), orally, using a conventional absorption promoter, nasally or as suppositories or topically, for example in the form of ophthalmic liquid, gel, preparation as an ointment or as a suspension, for example liposomal, as a formulation in microspheres or nanospheres, for example for instillation or injection subconjunctival or intra or peri ocular.
Secondo un ulteriore aspetto dell’ invenzione, viene fornita anche una composizione farmaceutica comprendente un coniugato od un complesso dei composti dell’invenzione insieme ad eccipienti o diluenti farmaceuticamente accettabili. Tali composizioni possono essere prodotte in modo convenzionale e possono essere presentate, ad esempio per la diagnostica per immagini, come un kit comprendente due dosaggi separati, uno essendo il radionuclide e l’altro il coniugato dei composti dell’invenzione, con istruzioni per la loro miscelazione. Per la radioterapia, il coniugato dei composti dell’invenzione in forma complessata può essere preferibilmente in forma di formulazione calda liquida. According to a further aspect of the invention, a pharmaceutical composition is also provided comprising a conjugate or a complex of the compounds of the invention together with pharmaceutically acceptable excipients or diluents. Such compositions can be produced in a conventional way and can be presented, for example for diagnostic imaging, as a kit comprising two separate assays, one being the radionuclide and the other the conjugate of the compounds of the invention, with instructions for their mixing. For radiotherapy, the conjugate of the compounds of the invention in complexed form can preferably be in the form of a hot liquid formulation.
I seguenti esempi intendono illustrare gli scopi della presente invenzione e non devono essere ritenuti in alcun modo limitativi della stessa. The following examples are intended to illustrate the purposes of the present invention and are not to be considered as limiting in any way.
Negli esempi saranno usate le seguenti abbreviazioni: The following abbreviations will be used in the examples:
l,4MNal 3-(l,4-dimetossi-Naftalen-2-il)-Alanine 2,5MhPhe 2,5-dimetossi-homoFenilalanina 3,8MNal 3-(3,8-dimetossi-Naftalen-2-il)-Alanine ACN Acetoni trile 1,4MNal 3- (1,4-Dimethoxy-Naphthalen-2-yl) -Alanine 2,5MhPhe 2,5-Dimethoxy-homoPhenylalanine 3,8MNal 3- (3,8-Dimethoxy-Naphthalen-2-yl) -Alanine ACN Acetones trile
Bn Benzile Bn Benzyl
Boc ter-Butilossi-carbonile Boc tert-Butyloxy-carbonyl
DIPEA Diisopropiletilammina DIPEA Diisopropylethylamine
DMF N,N-dimetilformammide DMF N, N-dimethylformamide
DPPA Difenilfosforilazide DPPA Diphenylphosphorylazide
DSC N,N-Disuccinimidilcarbonato DSC N, N-Disuccinimidylcarbonate
Fmoc Fluoren-9-il-metilossi-carbonile Fmoc-OSu Fluoren-9-il-metil, N-succinimidil carbonato HATU esafluorofosfato di 0-(7-Azabenzotriazol-lil)-N,N,N',N'-tetrametiluronio Fmoc Fluoren-9-yl-methyloxy-carbonyl Fmoc-OSu Fluoren-9-yl-methyl, N-succinimidyl carbonate HATU 0- (7-Azabenzotriazol-lil) hexafluorophosphate -N, N, N ', N'-tetramethyluronium
hPhe homoFenilalanina; acido 2-ammino-4-fenilbutirrico hPhe homoPhenylalanine; 2-amino-4-phenylbutyric acid
Hyp 4,Idrossi-prolina Hyp 4, Hydroxy-proline
Nal 3-(Naftalen-2-il)-Alanine; acido 2-ammino-3-naftalen-2-il-propionico Nal 3- (Naphthalen-2-yl) -Alanine; 2-amino-3-naphthalene-2-yl-propionic acid
NMM N-metil Morfolina NMM N-methyl Morpholine
Pd/C Palladio metallico su carbone Pd / C Metallic palladium on carbon
Phg Fenilglicina; acido 2-ammino-2-fenil-acetico PVDF Polivinilidenfluoruro Phg Phenylglycine; 2-amino-2-phenyl-acetic acid PVDF Polyvinylidene fluoride
Sty Stiril-Alanina; acido 2-ammino-5-fenil-pent-4-enoico Sty Stiril-Alanine; 2-amino-5-phenyl-pent-4-enoic acid
Tfa Trifluoroacetil Tfa Trifluoroacetyl
THF Tetraidrofurano THF Tetrahydrofuran
-Trt(Cl)-DVB Resina, (2-cloro)Tritil-Divinilbenzene Z Benzilossi-carbonile -Trt (Cl) -DVB Resin, (2-Chloro) Trityl-Divinylbenzene Z Benzyloxy-carbonyl
Salvo diversa indicazione, gli amminoacidi sono nella configurazione L; con (D/L) sono indicati gli amminoacidi racemi, mentre con (D,L) sono indicati i singoli enantiomeri di chiralità non definita. Unless otherwise stated, the amino acids are in the L configuration; the racemic amino acids are indicated with (D / L), while the single enantiomers of undefined chirality are indicated with (D, L).
Metodo generale di purificazione General method of purification
Se non altrimenti indicato, tutte le purificazioni finali sono state effettuate mediante un sistema HPLC/MS preparativo Waters con colonna Waters Symmetry C18 5 mm 19x50 mm, corredato di spettrometro di massa ZQ Waters. Unless otherwise indicated, all final purifications were performed using a Waters preparative HPLC / MS system with Waters Symmetry C18 5 mm 19x50 mm column, equipped with a Waters ZQ mass spectrometer.
Condizioni operative: Operating conditions:
Ionizzazione ES<+>centroide, tempo di scansione 15 min, scansione m/z 120-1000, tensione del cono (cone voltage) 15V, temperatura di sorgente 120°C, temperatura di solvatazione 250°C. ES ionization <+> centroid, scan time 15 min, scan m / z 120-1000, cone voltage 15V, source temperature 120 ° C, solvation temperature 250 ° C.
Eluenti HPLC: HPLC eluents:
A=H20, B=ACN, C=CF3COOH 1% in H20 A = H20, B = ACN, C = CF3COOH 1% in H20
Un’aliquota del prodotto grezzo da purificare è stata sciolta in MeOH e diluita con una miscela ACN/H20 (1:1; v/v). La soluzione, filtrata su membrana PVDF 0,45 mm, è stata iniettata nel sistema preparativo precedentemente descritto. Per ogni corsa, le frazioni corrispondenti al picco associato allo ione molecolare ([M+H]<~>) atteso sono state raccolte, riunite e concentrate a secchezza. Nel caso fossero presenti più picchi associati con lo stesso ione molecolare (isomeri) questi sono stati raccolti separatamente. An aliquot of the crude product to be purified was dissolved in MeOH and diluted with an ACN / H20 mixture (1: 1; v / v). The solution, filtered on a 0.45 mm PVDF membrane, was injected into the previously described preparative system. For each run, the fractions corresponding to the expected molecular ion-associated peak ([M + H] <~>) were collected, pooled and concentrated to dryness. If there were more peaks associated with the same molecular ion (isomers), these were collected separately.
Preparazione degli intermedi: Preparation of intermediates:
Esempio 1 Example 1
Fmoc-(D/L) 3-(3,8-dimetossi-Naftalen-2-il)-Alanina Fmoc- (D / L) 3- (3,8-dimethoxy-naphthalen-2-yl) -alanine
a) 3,8-dimetossi-2-naftaldeide (1 eq.), 2.2-dimetil-l,3-diossan-4,6-dione (1,35 eq.) e piperidina (0,12 eq.) sono sciolti in CHC13e la soluzione è scaldata a riflusso per 2.5 ore. Dopo lavaggi acquosi, il prodotto viene recuperato per evaporazione del solvente e ridisciolto in miscela di THF e metanolo, alla soluzione viene aggiunto NaBFfi (5,4 eq.). Dopo circa 10 minuti si aggiunge acqua e si acidifica a pH=3. Evaporando parzialmente, si separa un solido che viene recuperato e ridisciolto in etanolo, si aggiunge piridina e si scalda a riflusso fino a completa scomparsa del prodotto iniziale (controllo TLC). a) 3,8-dimethoxy-2-naphthaldehyde (1 eq.), 2.2-dimethyl-1,3-dioxane-4,6-dione (1.35 eq.) and piperidine (0.12 eq.) are dissolved in CHC13e the solution is refluxed for 2.5 hours. After aqueous washings, the product is recovered by evaporation of the solvent and redissolved in a mixture of THF and methanol, NaBFfi (5.4 eq.) Is added to the solution. After about 10 minutes, water is added and acidified to pH = 3. Partially evaporating, a solid is separated which is recovered and redissolved in ethanol, pyridine is added and heated under reflux until complete disappearance of the initial product (TLC control).
b) Dopo aver evaporato T etanolo, il prodotto (mono-etil estere dell’ acido 2-(3,8-Dimetossi-naftalen-2-il-metil)-malonico) viene sciolto in cloroformio e lavato con acqua acida. Alla soluzione anidrificata si aggiunge cloruro di tionile (1,3 eq.) e si scalda a riflusso per circa un’ora. Dopo ripetute evaporazioni del cloroformio, il residuo è sciolto in diclorometano e la soluzione è raffreddata in bagno di ghiaccio. Si aggiunge bromuro di tetrabutilammonio (catalitico) ed NaN3(1,2 eq.) sciolta in acqua, dopo due ore a 0°C, si recupera la fase organica, che viene lavata con acqua ed anidrificata con Na2S04anidro; la soluzione viene lasciata a temperatura ambiente, in presenza di Na2S04anidro, per tutta una notte. Alla soluzione filtrata si aggiunge acido trifluoroacetico (1,5 eq.) e si scalda a riflusso per circa 6 ore. Dopo aver lavato con NaHC03al 5%, si evapora il solvente e si purifica l’olio ottenuto su colonna di gel di silice. b) After evaporating T ethanol, the product (mono-ethyl ester of 2- (3,8-Dimethoxy-naphthalen-2-yl-methyl) -malonic acid) is dissolved in chloroform and washed with acidic water. Thionyl chloride (1.3 eq.) Is added to the anhydrified solution and heated under reflux for about an hour. After repeated evaporations of the chloroform, the residue is dissolved in dichloromethane and the solution is cooled in an ice bath. Tetrabutylammonium bromide (catalytic) and NaN3 (1.2 eq.) Dissolved in water are added, after two hours at 0 ° C, the organic phase is recovered, which is washed with water and anhydrified with Na2SO4anhydrous; the solution is left at room temperature, in the presence of Na2SO4 anhydrous, for a whole night. Trifluoroacetic acid (1.5 eq.) Is added to the filtered solution and heated under reflux for about 6 hours. After washing with 5% NaHC03, the solvent is evaporated and the oil obtained is purified on a silica gel column.
c) Il prodotto ottenuto (Tfa-(D/L)3,8MNal-OEt), viene sciolto in una miscela di THF, metanolo ed acqua, contenente K2C03(2 eq.) e scaldato a riflusso per una notte. La soluzione è parzialmente evaporata e si aggiunge Fmoc-OSu (1 eq.) sciolto in THF. A reazione completa (controllo TLC), il THF viene evaporato ed il prodotto recuperato estraendo la soluzione acquosa con etilacetato. Per aggiunta di n-esano si ottiene precipitazione del prodotto (Fmoc-(D/L)3,8MNal-OH), che viene filtrato ed essiccato (Purezza HPLC: 98.5%; m/z= 498 amu ([M+H]+)). c) The obtained product (Tfa- (D / L) 3.8MNal-OEt) is dissolved in a mixture of THF, methanol and water, containing K2C03 (2 eq.) and refluxed overnight. The solution is partially evaporated and Fmoc-OSu (1 eq.) Dissolved in THF is added. When the reaction is complete (TLC control), the THF is evaporated and the product recovered by extracting the aqueous solution with ethyl acetate. By adding n-hexane, precipitation of the product (Fmoc- (D / L) 3.8MNal-OH) is obtained, which is filtered and dried (HPLC purity: 98.5%; m / z = 498 amu ([M + H]) +)).
Esempio 2 Example 2
Fmoc- [4-(2-amminoetil)carb ammoil]Prolina Fmoc- [4- (2-aminoethyl) carb ammoyl] Proline
a) Z-Hyp-OBn e DSC (1 equivalente) sono sciolti in acetonitrile e trattati con trietilammina (1,2 eq.). Dopo una notte a temperatura ambiente, viene aggiunto N-Boc-diamminoetano (1,2 eq.) e si lascia reagire per 3,5 ore. Dopo evaporazione del solvente, il residuo ripreso con etilacetato viene lavato, nelTordine, con KHS04al 2.5%, NaHC03e NaCl. La soluzione organica, anidrificata con Na2S04anidro, è evaporata a secchezza recuperando il prodotto. a) Z-Hyp-OBn and DSC (1 equivalent) are dissolved in acetonitrile and treated with triethylamine (1.2 eq.). After one night at room temperature, N-Boc-diaminoethane (1.2 eq.) Is added and it is left to react for 3.5 hours. After evaporation of the solvent, the residue taken up with ethyl acetate is washed, in order, with KHS04 at 2.5%, NaHC03 and NaCl. The organic solution, dried with anhydrous Na2SO4, evaporated to dryness, recovering the product.
b) Il prodotto è sciolto in metanolo ed i gruppi protettori (Z ed estere benzilico) vengono rimossi mediante idrogenazione catalica in presenza di Pd/C al 10%. Dopo filtrazione del catalizzatore Tamminoacido viene recuperato, evaporando il solvente, e sciolto in una miscela di acqua e THF contenente K2C03(1 eq.), dopo aver raffreddato a 0°C viene aggiunto Fmoc-OSu (2 eq.) sciolto in THF. A reazione completa (controllo TLC), il THF viene evaporato ed il prodotto recuperato estraendo la soluzione acquosa con etilacetato. Per aggiunta di n-esano si ottiene precipitazione del prodotto, che viene filtrato ed essiccato (Purezza HPLC: 99,9%; m/z = 540 amu ([M+H]<+>)) b) The product is dissolved in methanol and the protecting groups (Z and benzyl ester) are removed by catalytic hydrogenation in the presence of 10% Pd / C. After filtration of the catalyst the amino acid is recovered, evaporating the solvent, and dissolved in a mixture of water and THF containing K2C03 (1 eq.), After having cooled to 0 ° C Fmoc-OSu (2 eq.) Dissolved in THF is added. When the reaction is complete (TLC control), the THF is evaporated and the product recovered by extracting the aqueous solution with ethyl acetate. Precipitation of the product is obtained by adding n-hexane, which is filtered and dried (HPLC purity: 99.9%; m / z = 540 amu ([M + H] <+>))
Esempio 3 Example 3
Fmoc-(D/L) 2,5-dimetossi-homoFenilalanina Fmoc- (D / L) 2,5-dimethoxy-homo-phenylalanine
a) Ad una sospensione di 2.2-dimetil-l,3-diosan-4,6-dione (1,3 eq.) in DMF (50 mL), raffreddata in bagno di ghiaccio, vengono aggiunti NaCNBH3(1,8 eq.) e 2,5-dimetossifenilacetaldeide (1,1 eq.). La miscela di reazione viene agitata a RT per 5h. Aggiungendo H20 si separa un solido che viene filtrato, purificato per cristallizzazione da isopropanolo ed infine sciolto in EtOH e trattato con piridina a riflusso per sei ore. a) NaCNBH3 (1.8 eq.) is added to a suspension of 2.2-dimethyl-1,3-diosan-4,6-dione (1.3 eq.) in DMF (50 mL), cooled in an ice bath. ) and 2,5-dimethoxyphenylacetaldehyde (1.1 eq.). The reaction mixture is stirred at RT for 5h. By adding H20 a solid is separated which is filtered, purified by crystallization from isopropanol and finally dissolved in EtOH and treated with pyridine at reflux for six hours.
b) Operando come descritto al punto b) dell’ esempio 1, dal prodotto ottenuto (mono-etil estere dell’acido 2-(2,5-Dimetossi-fenil-etil)-malonico) viene preparato Tammino acido parzialmente protetto Fmoc-(D/L)2,5MhPhe-OH (Purezza HPLC: 96%; m/z= 462 amu ([M+H]^). Esempio 4 b) Operating as described in point b) of example 1, the partially protected amino acid Fmoc- ( D / L) 2,5MhPhe-OH (HPLC purity: 96%; m / z = 462 amu ([M + H] ^). Example 4
Fmoc-(D/L) 3-(l,4-dimetossi-Naftalen-2-il)-Alanina Fmoc- (D / L) 3- (1,4-dimethoxy-Naphthalen-2-yl) -Alanine
Partendo da l,4-dimetossi-2-naftaldeide ed operando come descritto nell’esempio 1, si ottiene l’amminoacido protetto Fmoc-(D/L)l,4MNal-OH. (Purezza HPLC: 96,9%; m/z([M+H]+)= 498 amu). Starting from 1,4-dimethoxy-2-naphthaldehyde and operating as described in example 1, the protected amino acid Fmoc- (D / L) 1,4MNal-OH is obtained. (HPLC purity: 96.9%; m / z ([M + H] +) = 498 amu).
Preparazione dei ciclopeptidi: Preparation of cyclopeptides:
La purezza dei peptidi descritti negli esempi è stata analizzata mediante cromatografia HPLC in fase inversa (cromatografo Agilent 1100), usando il seguente metodo: The purity of the peptides described in the examples was analyzed by reverse phase HPLC chromatography (Agilent 1100 chromatograph), using the following method:
Eluenti: A) 0,1% TFA in acetonitrile/acqua (5:95; v/v) Eluents: A) 0.1% TFA in acetonitrile / water (5:95; v / v)
B) 0,1% TFA in acetonitrile B) 0.1% TFA in acetonitrile
Gradiente eluente B: da 20% a 80% in 30 min. Eluent gradient B: from 20% to 80% in 30 min.
Flusso: 1,0 ml/min. Flow: 1.0ml / min.
Colonna: Jupiter 4 μ (4 x 250 mm) Column: Jupiter 4 μ (4 x 250 mm)
Esempio 5 Example 5
ciclo[Tyr(Bn)-Phe-Pro(4-OCONH(CH2)2NH2)-Phe-(D,L)3,8MNal-Lys] isomero B cycle [Tyr (Bn) -Phe-Pro (4-OCONH (CH2) 2NH2) -Phe- (D, L) 3,8MNal-Lys] isomer B
a) H-Tyr(Bn)-Phe-Pro(4-OCONH(CH2)2NHBoc)-Phe-(D/L)3,8MNal-Lys(Boc)-OH a) H-Tyr (Bn) -Phe-Pro (4-OCONH (CH2) 2NHBoc) -Phe- (D / L) 3,8MNal-Lys (Boc) -OH
Partendo dalla resina Fmoc-Lys(Boc)-Trt(Cl)-DVB, si eseguono diversi cicli di sintesi peptidica in fase solida, fino ad ottenere l' esapeptide voluto; nel primo ciclo si usa Fmoc-(D/L)3,8Mnal-OH (vedi es. 1) e nel terzo ciclo si usa Fmoc-Pro(4-OCONH(CH2)2NHBoc)-OH (vedi es. 2); ad ogni ciclo il gruppo Fmoc viene rimosso con Piperidina al 20% in DMF e l amminoacido successivo, protetto come Fmoc, viene attivato con HATU e fatto reagire con i gruppi amminici presenti sulla resina. Starting from the Fmoc-Lys (Boc) -Trt (Cl) -DVB resin, several cycles of solid phase peptide synthesis are carried out, until the desired hexapeptide is obtained; in the first cycle we use Fmoc- (D / L) 3,8Mnal-OH (see example 1) and in the third cycle we use Fmoc-Pro (4-OCONH (CH2) 2NHBoc) -OH (see example 2); at each cycle the Fmoc group is removed with Piperidine at 20% in DMF and the subsequent amino acid, protected as Fmoc, is activated with HATU and reacted with the amino groups present on the resin.
Al termine il gruppo Fmoc viene rimosso con Piperidina al 20% in DMF ed il peptide parzialmente protetto viene rimosso dalla resina mediante un trattamento con una miscela di acido acetico, trifluoroetanolo e diclorometano (in proporzione 1:2:7) per 30 minuti a temperatura ambiente. Dopo aver evaporato il solvente, il residuo viene ripartito tra etilacetato e NaHC03al 5%, la fase organica viene recuperata ed evaporata ottenendo un residuo solido. At the end the Fmoc group is removed with Piperidine at 20% in DMF and the partially protected peptide is removed from the resin by a treatment with a mixture of acetic acid, trifluoroethanol and dichloromethane (in proportion 1: 2: 7) for 30 minutes at temperature environment. After evaporating the solvent, the residue is partitioned between ethyl acetate and 5% NaHC03, the organic phase is recovered and evaporated to obtain a solid residue.
b) ciclo[Tyr(Bn)-Phe-Pro(4-OCONH(CH2)2NH)-Phe-(D,L)3,8-MNal-Lys] Il peptide ottenuto in c) è sciolto in DMF (1,6 mM) e raffreddato a -10°C; si aggiungono DIPEA (2 eq) e DPPA (1,3 eq.) e si lascia a 4°C per 60 ore. Dopo aver allontanato la DMF, il residuo viene ripreso con etilacetato e lavato con NAHC03al 5%. Evaporando la fase organica, si ottiene un residuo solido che viene trattato con TFA (95% in H20) a 0°C per 1 ora e poi evaporato; nel residuo sono presenti diverse specie isomeriche che sono separate mediante cromatografia di fase inversa (colonna CI 8). Il secondo isomero, in ordine di eluizione dalla colonna HPLC, (isomero B) viene raccolto puro. b) cycle [Tyr (Bn) -Phe-Pro (4-OCONH (CH2) 2NH) -Phe- (D, L) 3,8-MNal-Lys] The peptide obtained in c) is dissolved in DMF (1, 6 mM) and cooled to -10 ° C; DIPEA (2 eq) and DPPA (1.3 eq.) are added and the mixture is left at 4 ° C for 60 hours. After removing the DMF, the residue is taken up with ethyl acetate and washed with NAHC03 at 5%. Evaporating the organic phase, a solid residue is obtained which is treated with TFA (95% in H20O) at 0 ° C for 1 hour and then evaporated; in the residue there are several isomeric species which are separated by reverse phase chromatography (column CI 8). The second isomer, in order of elution from the HPLC column, (isomer B) is collected pure.
HPLC: RT 14,74 min.; purezza 99,1% HPLC: RT 14.74 min .; purity 99.1%
MS: m/z = 1133 amu ([M+H]<+>) e 567 amu ([M+2H]<2+>) MS: m / z = 1133 amu ([M + H] <+>) and 567 amu ([M + 2H] <2+>)
Esempio 6 Example 6
ciclo[Tyr(Bn)-Phe-Pro(4-OCONH(CH2)2NH2)-Phe-(D,L)2,5MhPhe-Lys] isomero B cycle [Tyr (Bn) -Phe-Pro (4-OCONH (CH2) 2NH2) -Phe- (D, L) 2,5MhPhe-Lys] isomer B
a) H-Tyr(Bn)-Phe-Pro(4-OCONH(CH2)2NHBoc)-Phe-(D/L)2,5-MhPhe-Lys(Boc)-OH a) H-Tyr (Bn) -Phe-Pro (4-OCONH (CH2) 2NHBoc) -Phe- (D / L) 2,5-MhPhe-Lys (Boc) -OH
Si opera come descritto al punto a) delTesempio 5, utilizzando Fmoc-(D/L)2,5MhPhe-OH (es. 3) nel primo ciclo e Fmoc-Hyp-OH nel terzo ciclo. Prima della rimozione del gruppo Fmoc terminale, la resina viene trattata con p-nitrofenilcloroformiato (5 eq.) in presenza di NMM (5 eq.); dopo tre ore la resina è lavata con DCM e trattata con N-Boc-diamminoetano (5 eq.) per altre tre ore, quindi filtrata e lavata. Si procede quindi come descritto al punto a) dell’esempio 5. One operates as described in point a) of Example 5, using Fmoc- (D / L) 2,5MhPhe-OH (e.g. 3) in the first cycle and Fmoc-Hyp-OH in the third cycle. Before removing the terminal Fmoc group, the resin is treated with p-nitrophenylchloroformate (5 eq.) In the presence of NMM (5 eq.); after three hours the resin is washed with DCM and treated with N-Boc-diaminoethane (5 eq.) for another three hours, then filtered and washed. We then proceed as described in point a) of example 5.
b) ciclo[Tyr(Bn)-Phe-Pro(4-OCONH(CH2)2NH)-Phe-(D,L)2,5-MhPhe-Lys] Il peptide ottenuto in a) viene trattato come descritto al punto b) dell’esempio 5. Anche in questo caso si ottengono diversi isomeri, i quali sono separati mediante cromatografia di fase inversa (colonna CI 8). Il secondo isomero, in ordine di eluizione dalla colonna HPLC, (isomero B) viene raccolto puro. b) cycle [Tyr (Bn) -Phe-Pro (4-OCONH (CH2) 2NH) -Phe- (D, L) 2,5-MhPhe-Lys] The peptide obtained in a) is treated as described in point b ) of Example 5. Also in this case different isomers are obtained, which are separated by reverse phase chromatography (column CI 8). The second isomer, in order of elution from the HPLC column, (isomer B) is collected pure.
HPLC: RT 13,82 min.; purezza 99,0% HPLC: RT 13.82 min .; purity 99.0%
MS: m/z= 549 amu ([M+2H]<2+>) MS: m / z = 549 amu ([M + 2H] <2+>)
Esempio 7 Example 7
ciclo[Tyr(Bn)-Phe-Pro(4-OCONH(CH2)2NHCH3)-Phe-(D,L)3,8MNal-Lys] isomero B cycle [Tyr (Bn) -Phe-Pro (4-OCONH (CH2) 2NHCH3) -Phe- (D, L) 3,8MNal-Lys] isomer B
Si opera come descritto nell’esempio 6, utilizzando Fmoc-(D/L)3,8MNal-OH (es. 1) nel primo ciclo e Boc-N(CH3)-(CH2)2-NH2) per la modifica della catena laterale della idrossiprolina. Si ottengono diversi isomeri, i quali sono separati mediante cromatografia di fase inversa (colonna CI 8). Il secondo isomero, in ordine di eluizione dalla colonna HPLC, (isomero B) viene raccolto puro. We operate as described in example 6, using Fmoc- (D / L) 3,8MNal-OH (e.g. 1) in the first cycle and Boc-N (CH3) - (CH2) 2-NH2) for the modification of the chain side of hydroxyproline. Different isomers are obtained, which are separated by reverse phase chromatography (CI 8 column). The second isomer, in order of elution from the HPLC column, (isomer B) is collected pure.
HPLC: RT 15,07 min.; purezza 94,5% HPLC: RT 15.07 min .; purity 94.5%
MS: m/z= 1147 amu ([M+H]<~>) e 574 amu ([M+2H]<2+>MS: m / z = 1147 amu ([M + H] <~>) and 574 amu ([M + 2H] <2+>
Esempio 8 Example 8
ciclo[Tyr(Bn)-Phe-Pro(4-OCONH(CH2)2NH2)-Phe-(D,L)l,4-MNal-Lys] isomero A cycle [Tyr (Bn) -Phe-Pro (4-OCONH (CH2) 2NH2) -Phe- (D, L) 1,4-MNal-Lys] isomer A
Si opera come descritto nell’esempio 6, utilizzando Fmoc-(D/L)l,4MNal-OH (es. 4) nel primo ciclo. Si ottengono diversi isomeri, i quali sono separati mediante cromatografia di fase inversa (colonna CI 8). L’isomero con tempo di ritenzione inferiore (isomero A) corrisponde al prodotto del titolo. We operate as described in example 6, using Fmoc- (D / L) 1,4MNal-OH (ex. 4) in the first cycle. Different isomers are obtained, which are separated by reverse phase chromatography (CI 8 column). The isomer with the lower retention time (isomer A) corresponds to the title product.
HPLC: RT 13,71 min.; purezza 80,6% HPLC: RT 13.71 min .; purity 80.6%
MS: m/z= 1133 amu ([M+H]<~>) e 567 amu ([M+2H]<2+>)) MS: m / z = 1133 amu ([M + H] <~>) and 567 amu ([M + 2H] <2+>))
Esempio 9 Example 9
ciclo[Tyr(Bn)-Phe-Pro(4-OCONH(CH2)2NH2)-Phe-(D,L)l,4-MNal-Lys] isomero B cycle [Tyr (Bn) -Phe-Pro (4-OCONH (CH2) 2NH2) -Phe- (D, L) 1,4-MNal-Lys] isomer B
Dalla preparazione descritta nell’esempio precedente, si raccoglie puro anche l’isomero B, il secondo in ordine di eluizione dalla colonna HPLC. HPLC: RT 14,71 min.; purezza 97,7% From the preparation described in the previous example, isomer B is also collected pure, the second in order of elution from the HPLC column. HPLC: RT 14.71 min .; purity 97.7%
MS: m/z= 1133 amu ([M+H]<~>) e 567 amu ([M+2H]<2+>) MS: m / z = 1133 amu ([M + H] <~>) and 567 amu ([M + 2H] <2+>)
Esempio 10 Example 10
ciclo[Tyr(Bn)-Phe-Pro(4-OCONH(CH2)2NH2)-Phe-(D)Nal-Lys] cycle [Tyr (Bn) -Phe-Pro (4-OCONH (CH2) 2NH2) -Phe- (D) Nal-Lys]
Il composto viene sintetizzato seguendo la procedura descritta nell’esempio 6, utilizzando Fmoc-(D)Nal-OH nel primo ciclo. The compound is synthesized following the procedure described in example 6, using Fmoc- (D) Nal-OH in the first cycle.
HPLC: RT 14,14 min.; purezza 99,5% HPLC: RT 14.14 min .; purity 99.5%
MS: m/z= 1073 amu ([M+H]<~>) e 537 amu ([M+2H]<2+>) MS: m / z = 1073 amu ([M + H] <~>) and 537 amu ([M + 2H] <2+>)
Esempio 11 Example 11
ciclo[Tyr(Bn)-Phe-Pro(4-OCONH(CH2)2NH2)-Phe-(D)hPhe-Lys] cycle [Tyr (Bn) -Phe-Pro (4-OCONH (CH2) 2NH2) -Phe- (D) hPhe-Lys]
Il composto viene sintetizzato seguendo la procedura descritta nell’esempio 6, utilizzando Fmoc-(D)hPhe-OH nel primo ciclo. The compound is synthesized following the procedure described in example 6, using Fmoc- (D) hPhe-OH in the first cycle.
HPLC: RT 13,81 min.; purezza 94,5% HPLC: RT 13.81 min .; purity 94.5%
MS: m/z= 1037 amu ([M+H]<~>) e 519 amu ([M+2H]<2+>) MS: m / z = 1037 amu ([M + H] <~>) and 519 amu ([M + 2H] <2+>)
Esempio 12 Example 12
ciclo[Tyr(Bn)-Phe-Pro(4-OCONH(CH2)2NHCH3)-Phg-(D)Sty-Lys] Il composto viene sintetizzato seguendo la procedura descritta nell’esempio 7, utilizzando Fmoc-(D)Sty-OH nel primo ciclo e Fmoc-Phg-OH nel secondo ciclo. cycle [Tyr (Bn) -Phe-Pro (4-OCONH (CH2) 2NHCH3) -Phg- (D) Sty-Lys] The compound is synthesized following the procedure described in example 7, using Fmoc- (D) Sty- OH in the first cycle and Fmoc-Phg-OH in the second cycle.
HPLC: RT 13,62 min.; purezza 97,8% HPLC: RT 13.62 min .; purity 97.8%
MS: m/z= 1049 amu ([M+H]<~>) e 525 amu ([M+2H]<2+>) MS: m / z = 1049 amu ([M + H] <~>) and 525 amu ([M + 2H] <2+>)
Esempio 13 Example 13
ciclo[Tyr(Bn)-Phe-Pro(4-OCONH(CH2)2NH2)-Phg-(D)hPhe-Lys] cycle [Tyr (Bn) -Phe-Pro (4-OCONH (CH2) 2NH2) -Phg- (D) hPhe-Lys]
Il composto viene sintetizzato seguendo la procedura descritta nell’esempio 6, utilizzando Fmoc-(D)hPhe-OH nel primo ciclo e Fmoc-Phg-OH nel secondo ciclo. The compound is synthesized following the procedure described in example 6, using Fmoc- (D) hPhe-OH in the first cycle and Fmoc-Phg-OH in the second cycle.
HPLC: RT 12,78 min.; purezza 98,8% HPLC: RT 12.78 min .; purity 98.8%
MS: m/z=512 amu ([M+2H]<2+>) MS: m / z = 512 amu ([M + 2H] <2+>)
Esempio 14 Example 14
ciclo[Tyr(Bn)-Phe-Pro(4-OCONH(CH2)2NH2)-Tyr-(D,L)3,8MNal-Lys] isomero B cycle [Tyr (Bn) -Phe-Pro (4-OCONH (CH2) 2NH2) -Tyr- (D, L) 3,8MNal-Lys] isomer B
Si opera come descritto nell’esempio 5, utilizzando Fmoc-Tyr(tBu)-OH nel secondo ciclo. We operate as described in example 5, using Fmoc-Tyr (tBu) -OH in the second cycle.
HPLC: RT 13,13 min.; purezza 95,4% HPLC: RT 13.13 min .; purity 95.4%
MS: m/z = 1149 amu ([M+H]<+>) e 575 amu ([M+2H]<2+>) MS: m / z = 1149 amu ([M + H] <+>) and 575 amu ([M + 2H] <2+>)
Esempio 15 Example 15
ciclo[Ser(Bn)-Phe-Pro(4-OCONH(CH2)2NH2)-Phe-(D,L)3,8MNal-Lys] isomero B cycle [Ser (Bn) -Phe-Pro (4-OCONH (CH2) 2NH2) -Phe- (D, L) 3.8MNal-Lys] isomer B
Si opera come descritto nell’esempio 5, utilizzando Fmoc-Ser(Bn)-OH nel quinto ciclo. We operate as described in example 5, using Fmoc-Ser (Bn) -OH in the fifth cycle.
HPLC: RT 12,26 min.; purezza 98,2% HPLC: RT 12.26 min .; purity 98.2%
MS: m/z = 1057 amu ([M+H]<+>) e 529 amu ([M+2H]<2+>) MS: m / z = 1057 amu ([M + H] <+>) and 529 amu ([M + 2H] <2+>)
PARTE SPERIMENTALE EXPERIMENTAL PART
I composti dell’invenzione mostrano importanti proprietà farmacologiche come indicato in alcuni tests in vitro ed in vivo. The compounds of the invention show important pharmacological properties as indicated in some in vitro and in vivo tests.
In particolare, i composti dell’invenzione legano, con buona affinità, ad almeno uno dei sottotipi dei recettori della somatostatina. In particular, the compounds of the invention bind, with good affinity, to at least one of the subtypes of somatostatin receptors.
Saggi di binding Binding essays
I saggi di binding sono stati eseguiti, come spiegato di seguito, utilizzando preparazioni di recettori umani ricombinanti, hSSTRl, hSSTR2, hSSTR3 ed hSSTR5, ottenuti da membrane di cellule (p.e. CHO) transfettate secondo le metodiche standard. The binding assays were performed, as explained below, using recombinant human receptor preparations, hSSTR1, hSSTR2, hSSTR3 and hSSTR5, obtained from cell membranes (e.g. CHO) transfected according to standard methods.
Le membrane vengono incubate in duplicato per 60 min. a 25°C con 3-[125I]iodotirosill 1 Somatostatina- 14 (Amersham, IM161, 2000 Ci/mmol) come radioligando e con concentrazioni crescenti del composto in esame, in tampone Hepes 25 mM (pH 7.4), contenente MgCl25 mM, CaCl21 mM, 10 pg/ml di Saponina, 0.5% di BSA. L’incubazione viene terminata tramite filtrazione con un Filtermate Harvester (Perkin Elmer) attraverso filtri GF/B, che vengono poi lavati 6 volte con tampone (25 mM Hepes pH 7.4, 5 mM MgCl2, 1 mM CaCl2). La radioattività dei filtri viene contata in un lettore TopCountTM o un MicroBetaTM per 1 min/pozzetto dopo aver aggiunto il liquido di scintillazione Microscint 20 (Packard) ed incubato per 15 min. in un agitatore orbitale. I risultati sono espressi come percentuale di binding specifico del ligando radiomarcato, in presenza di concentrazioni crescenti del composto in esame. I valori di IC50 sono stati calcolati usando il software “GraphPad Prism” (IC50 = concentrazione di composto necessaria per ottenere metà della inibizione massima, nel test di binding competitivo descritto in precedenza). Membranes are incubated in duplicate for 60 min. at 25 ° C with 3- [125I] iodotirosill 1 Somatostatin- 14 (Amersham, IM161, 2000 Ci / mmol) as radioligand and with increasing concentrations of the test compound, in 25 mM Hepes buffer (pH 7.4), containing MgCl25 mM, CaCl21 mM, 10 pg / ml of Saponin, 0.5% of BSA. The incubation is terminated by filtration with a Filtermate Harvester (Perkin Elmer) through GF / B filters, which are then washed 6 times with buffer (25 mM Hepes pH 7.4, 5 mM MgCl2, 1 mM CaCl2). The radioactivity of the filters is counted in a TopCountTM reader or a MicroBetaTM for 1 min / well after adding Microscint 20 (Packard) scintillation liquid and incubated for 15 min. in an orbital shaker. The results are expressed as a percentage of specific binding of the radiolabelled ligand, in the presence of increasing concentrations of the compound under examination. The IC50 values were calculated using the “GraphPad Prism” software (IC50 = concentration of compound required to obtain half of the maximum inhibition, in the competitive binding test described above).
I valori delle IC50 dei composti dell’invenzione si collocano nel campo delle concentrazioni nMolari, preferibilmente sono compresi tra 0,1 e 50 nM. The values of the IC50 of the compounds of the invention lie in the range of nMolar concentrations, preferably they are between 0.1 and 50 nM.
IC50 (nM) IC50 (nM)
Composto hSSTRl hSSTR2 hSSTR3 hSSTR5 Esempio 5 10.8 9.3 0.31 0.42 Esempio 6 10.0 25.8 0.52 0.64 Esempio 7 5.8 9.2 1.33 0.97 Esempio 8 19.1 26.6 2.92 9.78 Esempio 9 32.4 9.9 2.34 1.90 Esempio 10 113.8 1.7 1.22 0.52 Esempio 11 26.9 21.3 1.34 1.18 Esempio 12 39.3 3.3 4.03 4.86 Esempio 13 84.7 31.9 3.02 0.54 Esempio 14 21.7 1.8 0.35 0.36 Esempio 15 1.0 7.0 1.80 1.62 Saggio per Tinibizione del rilascio di ormone della crescita su cellule pituitarie di ratto Compound hSSTRl hSSTR2 hSSTR3 hSSTR5 Example 5 10.8 9.3 0.31 0.42 Example 6 10.0 25.8 0.52 0.64 Example 7 5.8 9.2 1.33 0.97 Example 8 19.1 26.6 2.92 9.78 Example 9 32.4 9.9 2.34 1.90 Example 10 113.8 1.7 1.22 0.52 Example 11 26.9 21.3 1.34 1.18 Example 12 39.3 3.3 4.03 4.86 Example 13 84.7 31.9 3.02 0.54 Example 14 21.7 1.8 0.35 0.36 Example 15 1.0 7.0 1.80 1.62 Assay for inhibition of growth hormone release on rat pituitary cells
I composti delTinvenzione mostrano anche un’attività di inibizione del rilascio di ormone della crescita (GH), come evidenziato da test eseguiti in vitro su cellule pituitarie di ratto. Le ghiandole ipofisarie prelevate da ratti maschi adulti (CD1-SD, 175-200 g) vengono tagliate in piccoli pezzi ed incubate con collagenasi (1 mg/ml) in tampone Hank’s contenente 1% BSA, 20mM Hepes, antibiotici, per 20 min. a 37°C. Le cellule disperse, dopo essere state lavate più volte con tampone, vengono distribuite, a 20000 cellule/pozzetto, in piastre da 48 pozzetti e mantenute in coltura per 6-7 giorni (DMEM contenente 5% di siero fetale bovino, 5% di siero di cavallo, 1% di aminoacidi non essenziali). Nel giorno dell’ esperimento le cellule vengono lavate con tampone di Hank’s e poi incubate a 37°C per Ih in presenza di tampone di Hank’s addizionato di BSA 0,1% ed HEPES 20 mM. Il tampone viene poi sostituito con tampone fresco, sempre in presenza di BSA 0,1% ed HEPES 20 mM. Le cellule vengono quindi incubate per 3h a 37°C in incubatore a C02con varie concentrazioni dei prodotti in esame e con GHRH 3x10-9 M. Il GH rilasciato nel medium viene misurato utilizzando il Kit ELISA Rat Growth Hormone Biotrack Enzymeimmunoassay (Amersham RPN2561) o il Kit Mouse/Rat GH ELISA (DSL- 10-72100) secondo le indicazioni del fornitore. I composti dell’invenzione inibiscono il rilascio di GH a concentrazioni comprese tra 10-11 e 10-6 M; il composto dell’esempio 5 ha un valore di IC50 di 1,3 nM. The compounds of the invention also show an activity of inhibition of the release of growth hormone (GH), as evidenced by tests performed in vitro on rat pituitary cells. The pituitary glands taken from adult male rats (CD1-SD, 175-200 g) are cut into small pieces and incubated with collagenase (1 mg / ml) in Hank's buffer containing 1% BSA, 20mM Hepes, antibiotics, for 20 min. at 37 ° C. The dispersed cells, after being washed several times with buffer, are distributed, at 20,000 cells / well, in 48-well plates and kept in culture for 6-7 days (DMEM containing 5% fetal bovine serum, 5% serum horse, 1% non-essential amino acids). On the day of the experiment, the cells are washed with Hank's buffer and then incubated at 37 ° C for 1 h in the presence of Hank's buffer added with 0.1% BSA and 20 mM HEPES. The buffer is then replaced with fresh buffer, again in the presence of 0.1% BSA and 20 mM HEPES. The cells are then incubated for 3h at 37 ° C in a CO2 incubator with various concentrations of the test products and with GHRH 3x10-9 M. The GH released in the medium is measured using the ELISA Rat Growth Hormone Biotrack Enzymeimmunoassay Kit (Amersham RPN2561) or the Mouse / Rat GH ELISA Kit (DSL-10-72100) according to the supplier's instructions. The compounds of the invention inhibit the release of GH at concentrations between 10-11 and 10-6 M; the compound of example 5 has an IC50 value of 1.3 nM.
Saggio per Tinibizione del rilascio di ormone della crescita su cellule da adenoma ipofisario umano GH-secernente Assay for inhibition of growth hormone release on GH-secreting human pituitary adenoma cells
I composti dell’invenzione mostrano anche un’attività di inibizione del rilascio di GH da cellule di adenoma ipofisario umano GH-secernente, come indicato da test in vitro su reperti tumorali clinici. Il test viene eseguito utilizzando biopsie tumorali umane; il GH prodotto dalle cellule, non stimolate, in presenza di quantità variabili del composto in esame, viene misurato utilizzando il kit ELISA hGH - EASIA (biosource KAP1081) secondo le indicazioni del fornitore. Nei tumori sensibili all’azione di Somatostatina ed analoghi, i composti dell’invenzione dimezzano la produzione di GH a concentrazioni comprese tra 10-10 e 10-6 M; preferibilmente alla concentrazione di 10 nM. The compounds of the invention also show an inhibition activity of GH release from GH-secreting human pituitary adenoma cells, as indicated by in vitro tests on clinical tumor findings. The test is performed using human tumor biopsies; the GH produced by the cells, not stimulated, in the presence of variable quantities of the compound under examination, is measured using the ELISA hGH - EASIA kit (biosource KAP1081) according to the supplier's indications. In tumors sensitive to the action of Somatostatin and analogues, the compounds of the invention halve the production of GH at concentrations between 10-10 and 10-6 M; preferably at a concentration of 10 nM.
Saggio per Tinibizione in vivo della produzione di GH. stimolata da barbiturici Assay for in vivo inhibition of GH production. stimulated by barbiturates
I composti dell’ invenzione inibiscono, in vivo, il rilascio di GH stimolato dalla somministrazione di Nembutal. I composti sono somministrati sottocute, a diverse dosi, a ratti maschi (CD, Harlan Italy). Campioni di sangue vengono raccolti, a diversi tempi, un’ora dopo che gli animali siano stati anestetizzati mediante somministrazione intraperitoneale di Nembutal (60 mg/kg); i livelli di ormone vengono misurati mediante test ELISA. Negli animali trattati con i composti dell’invenzione, a dosi da 5 a 250 pg/kg, si nota una diminuzione dei livelli di GH prodotto. Il composto dell’esempio 1, alla dose di 5 pg/kg, riduce del 55% il rilascio di GH misurato sei ore dopo la somministrazione; alla dose di 125 pg/kg la riduzione di GH è ancora misurabile a 24 ore dalla somministrazione. The compounds of the invention inhibit, in vivo, the release of GH stimulated by the administration of Nembutal. The compounds are administered subcutaneously, at different doses, to male rats (CD, Harlan Italy). Blood samples are collected, at different times, one hour after the animals have been anesthetized by intraperitoneal administration of Nembutal (60 mg / kg); hormone levels are measured by ELISA test. In animals treated with the compounds of the invention, at doses from 5 to 250 pg / kg, there is a decrease in the levels of GH produced. The compound of Example 1, at a dose of 5 pg / kg, reduces the release of GH by 55% measured six hours after administration; at a dose of 125 pg / kg the reduction in GH is still measurable 24 hours after administration.
Saggio per il profilo farmacocinetico Assay for the pharmacokinetic profile
I composti dell’invenzione mostrano inoltre, nel ratto, un profilo farmacocinetico molto favorevole. Il profilo farmacocinetico è stato misurato somministrando i composti, per via sottocutanea, alla dose di 1 mg/kg, a ratti maschi (CD, Sprague Dawley; 200-250g). Campioni di sangue sono stati raccolti, a diversi tempi, fino a 72 ore dalla somministrazione. Le concentrazione del composto in esame sono state misurate, nei campioni di plasma separato, mediante un metodo di analisi LC-MS/MS ed i valori sono stati elaborati secondo un modello non compartimentale usando il software “Kinetica”. Nella seguente tabella sono riportati i principali parametri farmacocinetici ottenuti con il composto dell’esempio 1, confrontati con quelli ottenuti con PASIREOTIDE, un altro analogo stabile di somatostatina, attualmente in fase di sviluppo clinico (PASIREOTIDE è stato preparato seguendo la procedura descritta in W02002010192). The compounds of the invention also show, in the rat, a very favorable pharmacokinetic profile. The pharmacokinetic profile was measured by administering the compounds, subcutaneously, at a dose of 1 mg / kg, to male rats (CD, Sprague Dawley; 200-250g). Blood samples were collected at various times up to 72 hours after administration. The concentrations of the compound under examination were measured, in the separated plasma samples, by means of an LC-MS / MS analysis method and the values were processed according to a non-compartmental model using the “Kinetica” software. The following table shows the main pharmacokinetic parameters obtained with the compound of Example 1, compared with those obtained with PASIREOTIDE, another stable analogue of somatostatin, currently in clinical development (PASIREOTIDE was prepared following the procedure described in WO2002010192) .
Esemp. 5 PASIREOTIDE Example 5 PASIREOTIDE
Dose (mg/kg) 1 1 Dose (mg / kg) 1 1
Cmax (ng/mL) 224.02 667.88 Cmax (ng / mL) 224.02 667.88
tmax (h) 4 2 tmax (h) 4 2
tl/2 (h) 31.3 24.4 tl / 2 (h) 31.3 24.4
AUCO-t (ng/mL*h) 2728.50 2781.40 ;AUCtot (ng/mL*h) 2883.06 2795.85 AUCO-t (ng / mL * h) 2728.50 2781.40; AUCtot (ng / mL * h) 2883.06 2795.85
MRT (h) _ 18.96 4.87 MRT (h) _ 18.96 4.87
Il composto dell’esempio 5 risulta migliore di PASIREOTIDE sia in termini di tempo di dimezzamento, che come tempo medio di permanenza (MRT); nel caso di OCTREOTIDE, il valore di tl/2 è di circa 2 ore. The compound of example 5 is better than PASIREOTIDE both in terms of half-life and as an average residence time (MRT); in the case of OCTREOTIDE, the tl / 2 value is approximately 2 hours.
I composti dell’invenzione sono conseguentemente utili per la prevenzione o il trattamento dei disordini con un’origine che comprende o è associata ad un eccesso di secrezione di GH e/o un eccesso di IGF-1, come ad esempio nel trattamento dell’acromegalia, così come nel trattamento del diabete mellito di tipo I o di tipo II, specialmente nelle loro complicanze, quali ad esempio Tangiopatia, la retinopatia diabetica proliferativa, edema maculare diabetico, nefropatia e fenomeno dell’iperglicemia al risveglio e altri disordini metabolici collegati al rilascio di insulina o glucagone, come ad esempio l’obesità, ad esempio l’obesità morbosa o l’obesità ipotalamica o iperinsulenimica. I composti dell’invenzione sono utili anche nel trattamento delle fistole enterocutanee e pancreaticocutaneo, la sindrome di intestino irritabile, le malattie infiammatorie, come ad esempio la malattia di Grave, la malattia dell’intestino irritabile, la psoriasi o Tartrite reumatoide, la malattia del rene policistico, la sindrome da rapido svuotamento gastrico, sindrome da diarrea acquosa, diarrea collegata alTAIDS, diarrea indotta dalla chemioterapia, pancreatite acuta o cronica, tumori gastrointestinali ormone secemente (per esempio i tumori GEP, come vipomi, gluconomi, insulinomi, carcinoidi e simili), linfociti maligni, come linfomi o leucemie, carcinomi epatocellulari come il sanguinamento gastrointestinale, come il sanguinamento esofageo varicoso. The compounds of the invention are consequently useful for the prevention or treatment of disorders with an origin that includes or is associated with an excess of GH secretion and / or an excess of IGF-1, such as for example in the treatment of acromegaly. , as well as in the treatment of type I or type II diabetes mellitus, especially in their complications, such as for example tangiopathy, proliferative diabetic retinopathy, diabetic macular edema, nephropathy and hyperglycemia on awakening and other metabolic disorders related to the release of insulin or glucagon, such as obesity, for example morbid obesity or hypothalamic or hyperinsulenic obesity. The compounds of the invention are also useful in the treatment of enterocutaneous and pancreaticocutaneous fistulas, irritable bowel syndrome, inflammatory diseases, such as Grave's disease, irritable bowel disease, psoriasis or rheumatoid tarthritis, polycystic kidney, rapid gastric emptying syndrome, watery diarrhea syndrome, AIDS-related diarrhea, chemotherapy-induced diarrhea, acute or chronic pancreatitis, hormone secreted gastrointestinal tumors (e.g. GEP tumors, such as vipomas, gluconomas, insulinomas, carcinoids and the like ), malignant lymphocytes, such as lymphomas or leukemias, hepatocellular carcinomas such as gastrointestinal bleeding, such as varicose esophageal bleeding.
I composti dell’invenzione sono utili anche nel trattamento dei tumori positivi ai recettori per la somatostatina, come ad esempio i tumori che portano i recettori SSTR1, SSTR2, SSTR3 e/o SSTR5, come indicato nei test proliferativi con varie linee cellulari cancerose che esprimono i recettori per la somatostatina. The compounds of the invention are also useful in the treatment of somatostatin receptor positive tumors, such as tumors carrying SSTR1, SSTR2, SSTR3 and / or SSTR5 receptors, as indicated in proliferative tests with various cancerous cell lines expressing somatostatin receptors.
Per tutte le sopraccitate indicazioni il dosaggio richiesto varierà naturalmente in relazione, per esempio, al paziente, alla modalità di somministrazione ed alla severità delle condizioni che devono essere trattate. In generale comunque si ottengono dei risultati soddisfacenti con somministrazioni da 1 pg fino a 0,7 mg/kg/giornalieri dei composti dell’invenzione. Un dosaggio indicativo giornaliero per pazienti è nell’ordine da circa 2 pg fino a 50 mg, preferibilmente da circa 0,01 a circa 40 mg, per esempio da circa 0,001 a circa 3 mg s.c. del composto convenientemente somministrato in dosi divise fino a 3 volte al giorno in forme di dosaggio unitarie contenenti per esempio da circa 0,5 pg a circa 25 mg, per esempio da circa 2 pg a circa 20 mg, per esempio da circa 2 pg a circa 1,5 mg dei composti dell’ invenzione. For all the aforementioned indications, the dosage required will naturally vary in relation, for example, to the patient, the mode of administration and the severity of the conditions to be treated. In general, however, satisfactory results are obtained with administrations from 1 pg up to 0.7 mg / kg / day of the compounds of the invention. An indicative daily dosage for patients is in the order of about 2 pg up to 50 mg, preferably from about 0.01 to about 40 mg, for example from about 0.001 to about 3 mg s.c. of the compound conveniently administered in divided doses up to 3 times a day in unit dosage forms containing for example from about 0.5 pg to about 25 mg, for example from about 2 pg to about 20 mg, for example from about 2 pg to about 1.5 mg of the compounds of the invention.
I coniugati dei composti dell’invenzione o i loro sali farmaceuticamente accettabili sono utili sia come agenti per la diagnostica per immagini, per esempio per la visualizzazione dei tessuti e delle cellule positivi ai recettori per la somatostatina, come i tumori e le metastasi positivi ai recettori per la somatostatina, sia per i disordini infiammatori o autoimmuni che mostrano recettori per la somatostatina, la tubercolosi o il rigetto di organi dopo trapianto, quando complessate con un elemento rivelabile, come ad esempio i nuclidi γ o positroni emittenti, uno ione di metallo fluorescente o uno ione paramagnetico, come ad esempio<m>In,<161>Tb,<177>Lu,<68>Ga, Eu<3+>, Gd<3+>, Fe<3+>, Mn<2+>o Cr<2+>, o come radiofarmaceutici per il trattamento in vivo dei tumori e delle metastasi positivi ai recettori per la somatostatina, per Tartite reumatoide, e le condizioni di infiammazione severa, quando complessati con un nuclide a- o β-emittente con cascata di elettroni Auger, per esempio<90>Y,<161>Tb,<177>LU,<211>At,<213>Bi oppure<201>T1. The conjugates of the compounds of the invention or their pharmaceutically acceptable salts are useful both as diagnostic imaging agents, for example for visualizing somatostatin receptor-positive tissues and cells, such as tumors and receptor-positive metastases for somatostatin, either for inflammatory or autoimmune disorders showing somatostatin receptors, tuberculosis or organ rejection after transplantation, when complexed with a detectable element, such as γ nuclides or positron-emitting, a fluorescent metal ion or a paramagnetic ion, such as <m> In, <161> Tb, <177> Lu, <68> Ga, Eu <3+>, Gd <3+>, Fe <3+>, Mn <2+> or Cr <2+>, or as radiopharmaceuticals for the in vivo treatment of somatostatin receptor positive tumors and metastases, for rheumatoid tartitis, and conditions of severe inflammation, when complexed with an a- or β-emitting nuclide with Auger electron cascade, for example <90> Y, <161> Tb, <177> LU, <211> At, <213> Bi or <201> T1.
I coniugati dei composti dell’invenzione in forma complessata per uso nella diagnostica per immagini possono essere somministrati per esempio per via intravenosa, per esempio in forma di soluzioni iniettabili o sospensioni, preferibilmente in forma di singola iniezione. I radiotraccianti possono preferibilmente essere realizzati poco prima della somministrazione al paziente. The conjugates of the compounds of the invention in complexed form for use in diagnostic imaging can be administered for example intravenously, for example in the form of injectable solutions or suspensions, preferably in the form of a single injection. The radiotracers can preferably be made shortly before administration to the patient.
Negli animali un intervallo indicativo di dosaggio può essere da 0,01 a 1 pg/kg di coniugato dei composti dell’invenzione, complessato con 0,02 0,5 mCi di radionuclide γ-emettente. Nei mammiferi più grandi, come ad esempio gli umani, un intervallo di dosaggio indicativo può essere da 1 a 100 pg/m<2>di coniugato dei composti delTinvenzione complessato per esempio con da 1 a 100 mCi/m<2>di elemento rivelabile, come ad esempio 111T, 86vY o 177TIn Lu. In animals, an indicative dosage range can be from 0.01 to 1 pg / kg of conjugate of the compounds of the invention, complexed with 0.02 0.5 mCi of γ-emitting radionuclide. In larger mammals, such as humans, an indicative dosage range can be from 1 to 100 pg / m <2> of conjugate of the compounds of the invention complexed for example with from 1 to 100 mCi / m <2> of detectable element , such as 111T, 86vY or 177TIn Lu.
I dosaggi utilizzati nella pratica dell’uso radioterapico della presente invenzione dipenderanno, ovviamente, in relazione alle particolari condizioni che dovranno essere trattate, per esempio la radiotossicità nota per gli organi sani che esprimono i recettori per la somatostatina, la grandezza della massa tumorale e la terapia desiderata. In generale la dose è calcolata sulla base dei dati di farmacocinetica e di distribuzione della radioattività ottenuti da organi sani e basati sull’uptake osservato sul bersaglio. Un complesso β-emittente o un coniugato dei composti delTinvenzione possono essere ripetutamente somministrati, per esempio per un periodo da 1 a 3 mesi. The dosages used in the practice of radiotherapeutic use of the present invention will obviously depend on the particular conditions to be treated, for example the known radiotoxicity for healthy organs that express somatostatin receptors, the size of the tumor mass and the desired therapy. In general, the dose is calculated on the basis of pharmacokinetic and radioactivity distribution data obtained from healthy organs and based on the observed uptake on the target. A β-emitter complex or a conjugate of the compounds of the invention can be repeatedly administered, for example for a period of 1 to 3 months.
Negli animali un intervallo di dosaggio indicativo può essere da 20 a 100 pg/kg di coniugato dei composti delTinvenzione complessati con da 15 a 70 mCi di un nuclide α- o β- emittente, od un nuclide con la cascata di elettroni Auger, come ad esempio<90>Y,<177>Lu o<161>Tb. Nei mammiferi più grandi, come gli uomini, un intervallo di dosaggio indicativo può essere da 1 a 100 p/m<2>di un composto delTinvenzione coniugato complessato, per esempio con da 1 a 100 mCi/m<2>di un nuclide α- o β- emittente o un nuclide con cascata di elettroni Auger, ad esempio<90>Y,<177>Lu o<161>Tb. In animals, an indicative dosage range can be from 20 to 100 pg / kg of conjugate of the compounds of the invention complexed with from 15 to 70 mCi of an α- or β-emitting nuclide, or a nuclide with the Auger electron cascade, such as example <90> Y, <177> Lu or <161> Tb. In larger mammals, such as humans, an indicative dosage range may be from 1 to 100 p / m <2> of a complexed conjugate compound of the invention, for example with from 1 to 100 mCi / m <2> of an α nuclide - or β- emitter or a nuclide with Auger electron cascade, for example <90> Y, <177> Lu or <161> Tb.
I coniugati dei composti delTinvenzione in forma complessata per l’uso come agenti radioterapici possono essere somministrati attraverso ogni via convenzionale, per esempio la via intravenosa, per esempio nella forma di soluzioni iniettabili. Può essere somministrata vantaggiosamente per infusione, per esempio con un’infusione da 15 a 60 minuti. A seconda del sito del tumore, può essere somministrato il più vicino possibile al sito del tumore, per esempio attraverso un catetere. La presente invenzione fornisce anche una composizione farmaceutica comprendente un coniugato dei composti dell’invenzione in forma di base libera o come sale farmaceuticamente accettabile o come complesso con un agente rivelabile o radioterapeutico, insieme ad uno o più eccipienti o diluenti farmaceuticamente accettabili. The conjugates of the compounds of the invention in complexed form for use as radiotherapeutic agents can be administered through any conventional route, for example the intravenous route, for example in the form of injectable solutions. It can be advantageously administered by infusion, for example with an infusion of 15 to 60 minutes. Depending on the tumor site, it can be administered as close to the tumor site as possible, for example through a catheter. The present invention also provides a pharmaceutical composition comprising a conjugate of the compounds of the invention in the form of a free base or as a pharmaceutically acceptable salt or as a complex with a detectable or radiotherapeutic agent, together with one or more pharmaceutically acceptable excipients or diluents.
I composti dell’invenzione o i loro coniugati in forma complessata sono utili per mappare o trattare i tumori che esprimono o che accumulano i recettori, come i tumori pituitari, gastro-entero pancreatici, i carcinoidi, i tumori del sistema nervoso centrale, del seno, prostatici (incluso il cancro alla prostata ormone-refrattario avanzato), i tumori ovarici o del colon, il tumore delle piccole cellule del polmone, nell’occlusione intestinale maligna, paragangliosomi, il cancro al rene, il cancro alla pelle, i neuroblastomi, i feocromocitomi, i carcinoma midollare della tiroide, i mieloma, i linfoma, i linfoma Hodgkins e non-Hodgkins, i tumori delle ossa e le loro metastasi, così come i disordini autoimmuni o infiammatori, ad esempio l’artrite reumatoide, la malattia di Graves o altri malattie infiammatorie dell’occhio. The compounds of the invention or their conjugates in complexed form are useful for mapping or treating tumors that express or accumulate receptors, such as pituitary tumors, gastro-entero-pancreatic tumors, carcinoids, tumors of the central nervous system, breast, prostate cancer (including advanced hormone-refractory prostate cancer), colon or ovarian cancers, small cell lung cancer, malignant intestinal obstruction, paragangliosomes, kidney cancer, skin cancer, neuroblastomas, pheochromocytomas, medullary thyroid carcinoma, myeloma, lymphoma, Hodgkins and non-Hodgkins lymphoma, bone tumors and their metastases, as well as autoimmune or inflammatory disorders, eg rheumatoid arthritis, Graves' disease or other inflammatory eye diseases.
I composti dell’invenzione o i loro coniugati complessati possono essere somministrati come unico principio attivo oppure possono essere somministrati in combinazione, per esempio come adiuvanti, ad altri principi attivi. Per esempio possono essere usati in combinazione con un agente immunosoppressivo, ad esempio un inibitore della calcineurina, come la ciclosporina A o FK506; con un lattone macrociclico avente proprietà immunosoppressive, come la rapamicina; con un anticorpo monoclonale con proprietà immunosoppressive o con un agente antiinfiammatorio. The compounds of the invention or their complexed conjugates can be administered as a single active ingredient or can be administered in combination, for example as adjuvants, with other active ingredients. For example they can be used in combination with an immunosuppressive agent, for example a calcineurin inhibitor, such as cyclosporine A or FK506; with a macrocyclic lactone having immunosuppressive properties, such as rapamycin; with a monoclonal antibody with immunosuppressive properties or with an anti-inflammatory agent.
I composti dell’ invenzione o i loro coniugati complessati possono essere usati anche in combinazione con un agente antiproliferativo, per esempio un principio attivo chemoterapeutico, come il paclitaxel, la gemcitabina, il cisplatino, la doxorubicina, il 5-fluorouracile o il taxolo, con un agente ormonale o antagonista, per esempio un antiandrogeno o il mitoxantrone (specialmente nel caso di cancro alla prostata) o con un antiestrogeno, come il letrozolo (specialmente nei casi di cancro al seno), con un antimetabolita, con un alcaloide da una pianta, con un modificatore di risposte biologiche, preferibilmente un interferone od una linfochina, con un inibitore delle chinasi proteiche della tirosina e/o con le chinasi di serina/treonina, con un enzima inibitore della istoni-deacetilasi o con un agente con altri o sconosciuti meccanismi d’azione, come ad esempio l’aniepotilone o i derivati delTepotilone, o con un lattone macrociclico come ad esempio la rapamicina, RAD oppure CCI779. The compounds of the invention or their complexed conjugates can also be used in combination with an antiproliferative agent, for example a chemotherapeutic active ingredient, such as paclitaxel, gemcitabine, cisplatin, doxorubicin, 5-fluorouracil or taxol, with a hormonal agent or antagonist, for example an antiandrogen or mitoxantrone (especially in the case of prostate cancer) or with an antiestrogen, such as letrozole (especially in cases of breast cancer), with an antimetabolite, with an alkaloid from a plant, with a biological response modifier, preferably an interferon or a lymphokine, with a tyrosine protein kinase inhibitor and / or with serine / threonine kinases, with a histone-deacetylase inhibitor enzyme or with an agent with other or unknown mechanisms of action, such as for example aniepotilone or the derivatives of Tepothilone, or with a macrocyclic lactone such as rapamycin, RAD or CCI779.
Quando i composti dell’invenzione o i loro coniugati nella forma complessata sono somministrati in combinazione con un altro farmaco, i dosaggi dei farmaci co-somministrati varieranno, ovviamente, in funzione del tipo di combinazione utilizzata, dello specifico farmaco impiegato, delle condizioni da trattare e così via. I termini “co-somministrazione” o (somministrazione combinata” o simili sono qui utilizzati per comprendere una somministrazione degli agenti terapeutici selezionati ad un singolo paziente, ed intendono includere i regimi di trattamento in cui gli agenti non sono necessariamente somministrati per la stessa via di somministrazione o allo stesso tempo. When the compounds of the invention or their conjugates in the complexed form are administered in combination with another drug, the dosages of the co-administered drugs will obviously vary according to the type of combination used, the specific drug used, the conditions to be treated and etc. The terms "co-administration" or (combined administration "or the like are used herein to encompass an administration of the selected therapeutic agents to an individual patient, and are intended to include treatment regimens in which the agents are not necessarily administered by the same route of administration or at the same time.
La particolare combinazione dell’ invenzione sarà selezionata a seconda che si debba prevenire o trattare la malattia o il disordine; per esempio una combinazione con un agente immunosoppressivo ad esempio per la prevenzione o il trattamento del rigetto cronico dei trapianti, una combinazione con un secretagogo dell’ insulina, con un promotore della secrezione dell’insulina, con un sensibilizzante dell’insulina o con una bassa dose di insulina nel trattamento del diabete e nelle sue complicazioni, una combinazione con un agente antiinfiammatorio per la prevenzione ed il trattamento delle malattie o dei disordini infiammatori, una combinazione con un agente con effetto anti-angiogenico per la prevenzione o il trattamento per esempio dell’edema maculare o la degenerazione o il cancro, una combinazione con un agente chemioterapico per l’uso nel cancro. The particular combination of the invention will be selected according to whether the disease or disorder is to be prevented or treated; for example a combination with an immunosuppressive agent e.g. for the prevention or treatment of chronic transplant rejection, a combination with an insulin secretagogue, an insulin secretion promoter, an insulin sensitizer or a low insulin dose in the treatment of diabetes and its complications, a combination with an anti-inflammatory agent for the prevention and treatment of inflammatory diseases or disorders, a combination with an anti-angiogenic agent for the prevention or treatment of e.g. macular edema or degeneration or cancer, a combination with a chemotherapeutic agent for use in cancer.
Claims (40)
Priority Applications (16)
Application Number | Priority Date | Filing Date | Title |
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ITMI20072266 ITMI20072266A1 (en) | 2007-12-03 | 2007-12-03 | NEW NON-SELECTIVE SOMATOSTATINE ANALOGUES |
ES08856519T ES2431573T3 (en) | 2007-12-03 | 2008-11-24 | New non-selective somatostatin analogues |
PCT/EP2008/066081 WO2009071460A2 (en) | 2007-12-03 | 2008-11-24 | New non-selective somatostatin analogues |
PT88565197T PT2225271E (en) | 2007-12-03 | 2008-11-24 | New non-selective somatostatin analogues |
CN200880118937.1A CN101883785B (en) | 2007-12-03 | 2008-11-24 | New non-selective somatostatin analogues |
JP2010535349A JP5331817B2 (en) | 2007-12-03 | 2008-11-24 | Novel non-selective somatostatin analogues |
US12/734,475 US8937152B2 (en) | 2007-12-03 | 2008-11-24 | Non-selective somatostatin analogues |
PL08856519T PL2225271T3 (en) | 2007-12-03 | 2008-11-24 | New non-selective somatostatin analogues |
EP08856519.7A EP2225271B1 (en) | 2007-12-03 | 2008-11-24 | New non-selective somatostatin analogues |
CA2702940A CA2702940C (en) | 2007-12-03 | 2008-11-24 | New non-selective somatostatin analogues |
BRPI0818978A BRPI0818978B8 (en) | 2007-12-03 | 2008-11-24 | new non-selective somatostatin analogues |
SI200831046T SI2225271T1 (en) | 2007-12-03 | 2008-11-24 | New non-selective somatostatin analogues |
DK08856519.7T DK2225271T3 (en) | 2007-12-03 | 2008-11-24 | NEW NON-SELECTIVE SOMATOSTATIN ANALOGS |
KR1020107010880A KR101500528B1 (en) | 2007-12-03 | 2008-11-24 | New non-selective somatostatin analogues |
HRP20130948AT HRP20130948T1 (en) | 2007-12-03 | 2013-10-07 | New non-selective somatostatin analogues |
CY20131100895T CY1114490T1 (en) | 2007-12-03 | 2013-10-10 | NEW NON-OPTIONAL SOMATOSTATIN analogues |
Applications Claiming Priority (1)
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ITMI20072266 ITMI20072266A1 (en) | 2007-12-03 | 2007-12-03 | NEW NON-SELECTIVE SOMATOSTATINE ANALOGUES |
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