ITNA20090047A1 - ANTITUMORAL AGENTS WITH INHIBITIVE ACTIVITY OF PRENILATION PROTEINS, PREPARATION PROCESS AND USE IN THE MEDICAL FIELD - Google Patents
ANTITUMORAL AGENTS WITH INHIBITIVE ACTIVITY OF PRENILATION PROTEINS, PREPARATION PROCESS AND USE IN THE MEDICAL FIELD Download PDFInfo
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- ITNA20090047A1 ITNA20090047A1 IT000047A ITNA20090047A ITNA20090047A1 IT NA20090047 A1 ITNA20090047 A1 IT NA20090047A1 IT 000047 A IT000047 A IT 000047A IT NA20090047 A ITNA20090047 A IT NA20090047A IT NA20090047 A1 ITNA20090047 A1 IT NA20090047A1
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- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 description 1
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/4015—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
Description
DESCRIZIONE dell’invenzione avente per TITOLO: “Inibitori di proteine di premiazione come agenti antitumorali: processo di preparazione ed impieghi in campo medico”, DESCRIPTION of the invention with TITLE: "Prize protein inhibitors as anticancer agents: preparation process and uses in the medical field",
composti della presente invenzione, non limitati a quelli indicati negli esempi, sono utili per il trattamento del cancro causato o aggravato dalla sovraespressione di Ras e di altre proteine di famesilazione. Approssimativamente il 25% di tutti i tumori umani è dovuto a geni mutanti che codificano forme mutanti (H-/Ras, K -Ras, N -Ras) di una proteina nota come Ras. Questa proteina è sovraespressa nello sviluppo di numerosi tumori maligni, [a) Rodenhuis, ras and human tumore, Semin Cancer Biol 3 (1992), pp. 241-247. b) J.L. Bos, ras oncogenes in human cancer: a review, Cancer Res 49 (1989), pp. 4682-4689.] Casistiche riguardanti adenocarcinomi del colon, del pancreas e del polmone riportano alterazioni di K-ras fino al 90%, con implicazioni fondamentali nei processi di tumorigenesi. Il concetto fondamentale è che le oncoproteine Ras attivate sono in grado di eludere il controllo inibitorio delle guanosintrifosfatasi (GTPasi). Le cellule tumorali rimangono così in un perenne stato proliferativo. Per indurre la divisione cellulare, Ras deve essere localizzata sulla superficie interna della membrana delle cellule cancerose. Questa allocazione di Ras sulla membrana è dovuta al legame di un gruppo idrofobico, principalmente il famesolo, ma anche il geranilgeranile. In entrambi i casi, il gruppo idrofobico si lega a Ras per via enzimatica in un processo noto come prenilazione. Pertanto, interferire con la prenilazione di Ras può prevenire la allocazione di Ras sulla superfìcie interna della membrana cellulare tumorale con conseguente blocco della divisione cellulare incontrollata e/o ritorno della cellula cancerosa al fenotipo normale [a) M.S. Boguski et al. Proteine regulating Ras and its relatives, Nature 366 (1993), pp. 643-654. b) R. Khosravi-Far et al. Protein prenylation: key to ras function and cancer intervention?, Celi Growth Differ 3 (1992), pp. 461-469.]. L’enzima che lega il gruppo prenile a Ras, RhoB ed altre proteine per facilitarne l’adatta allocazione nella cellula è la proteina famesil transferasi (riferita qui come FTasi). Il gruppo prenile si lega a Ras, RhoB e ad altre proteine per reazione con il famesildifosfato, anche noto come famesil pirofosfato (qui riferito come FPP). In altre parole, la FTasi catalizza la reazione illustrata sotto per la proteina Ras, nella quale la proteina si lega al gruppo famesile [a) End D.W. et al. Famesyl protein transferase inhibitors: molecular mechanisms and progress in thè clinic. Top Med Chem (2007) 1: 133-168. b) D.W. End et al. Famesyl protein transferase inhibitors and other therapies targeting thè Ras signal transduction pathway, Invest New Drugs 17 (1999), pp. 241-258. c) E.K. Rowinsky et al. Ras protein famesyltransferase: A strategie target for anticancer therapeutic development, J Clin Oncol 17 (1999), pp. 3631— 3652.] per spostamento del gruppo pirofosfato (P207<4'>, riferito qui come PP,): compounds of the present invention, not limited to those indicated in the examples, are useful for the treatment of cancer caused or aggravated by the overexpression of Ras and other famesylation proteins. Approximately 25% of all human cancers are due to mutant genes that encode mutant forms (H- / Ras, K -Ras, N -Ras) of a protein known as Ras. This protein is overexpressed in the development of numerous malignant tumors, [a) Rodenhuis, ras and human tumor, Semin Cancer Biol 3 (1992), pp. 241-247. b) J.L. Bos, ras oncogenes in human cancer: a review, Cancer Res 49 (1989), pp. 4682-4689.] Cases concerning adenocarcinomas of the colon, pancreas and lung report K-ras alterations up to 90%, with fundamental implications in tumorigenesis processes. The fundamental concept is that activated Ras oncoproteins are able to evade the inhibitory control of guanosynthriphosphatases (GTPases). The tumor cells thus remain in a perennial proliferative state. To induce cell division, Ras must be located on the inner surface of the cancer cell membrane. This allocation of Ras on the membrane is due to the binding of a hydrophobic group, mainly famesol, but also geranylgeranyl. In both cases, the hydrophobic group binds to Ras enzymatically in a process known as prenylation. Therefore, interfering with Ras prenylation can prevent the allocation of Ras on the inner surface of the tumor cell membrane with consequent blocking of uncontrolled cell division and / or return of the cancer cell to the normal phenotype [a) M.S. Boguski et al. Proteine regulating Ras and its relatives, Nature 366 (1993), pp. 643-654. b) R. Khosravi-Far et al. Protein prenylation: key to ras function and cancer intervention ?, Celi Growth Differ 3 (1992), pp. 461-469.]. The enzyme that binds the prenyl group to Ras, RhoB and other proteins to facilitate their proper allocation in the cell is the famesyl transferase protein (referred to here as FTase). The prenyl group binds to Ras, RhoB and other proteins by reaction with famesyldiphosphate, also known as famesyl pyrophosphate (referred to here as FPP). In other words, FTase catalyzes the reaction illustrated below for the Ras protein, in which the protein binds to the famesyl group [a) End D.W. et al. Famesyl protein transferase inhibitors: molecular mechanisms and progress in the clinic. Top Med Chem (2007) 1: 133-168. b) D.W. End et al. Famesyl protein transferase inhibitors and other therapies targeting the Ras signal transduction pathway, Invest New Drugs 17 (1999), pp. 241-258. c) E.K. Rowinsky et al. Ras protein famesyltransferase: A target strategies for anticancer therapeutic development, J Clin Oncol 17 (1999), pp. 3631— 3652.] by displacement of the pyrophosphate group (P207 <4 '>, referred to here as PP,):
FTasi FTase
Ras FPP ...→ ... farnesi PP, Ras FPP ... → ... farnesi PP,
Ciò detto, l’enzima FTasi è un bersaglio chiave nella strategia che tende a ritardare la proliferazione cellulare. Mediante la regolazione dell’attività della FTasi, la famesilazione di Ras, la famesilazione e geranilgeranilazione di RhoB e la premiazione di altre proteine possono essere controllate. Questo può anche alterare la distribuzione intracellulare di queste proteine e, a sua volta, prevenire la proliferazione delle cellule cancerose. That said, the FTase enzyme is a key target in the strategy that tends to delay cell proliferation. By regulating the activity of FTase, the famesylation of Ras, the famesylation and geranylgeranylation of RhoB and the rewarding of other proteins can be controlled. This can also alter the intracellular distribution of these proteins and, in turn, prevent the proliferation of cancer cells.
Molte sostanze sono note per bloccare l’attività della FTasi e prevenire la famesilazione di proteine cellulari. Queste includono inibitori della i) FTasi (FTI), che generalmente agiscono bloccando il legame delle proteine che devono essere premiate, ii) FPP o iii) entrambi, nel sito attivo della FTasi. Senza la capacità dei normali substrati (ad es. Ras ed FPP) di legarsi alla FTasi, questo enzima non può provvedere al trasferimento del gruppo famesile da FPP a Ras. In generale, gli inibitori strutturalmente mimano uno o entrambi i substrati naturali dell’enzima, in questo caso Ras e/o FPP. Many substances are known to block the activity of FTase and prevent the famesilation of cellular proteins. These include i) FTase inhibitors (FTIs), which generally work by blocking the binding of proteins to be rewarded, ii) FPP or iii) both, at the active site of FTase. Without the ability of normal substrates (eg Ras and FPP) to bind to FTase, this enzyme cannot provide for the transfer of the famesyl group from FPP to Ras. In general, the inhibitors structurally mimic one or both of the natural substrates of the enzyme, in this case Ras and / or FPP.
Poiché il processo di famesilazione risulta fondamentale nell'attività delle oncoproteine Ras, l'inibizione specifica della FTasi è una strategia terapeutica potenzialmente efficace. Inoltre permetterebbe di agire con le funzioni delle cellule tumorali senza influenzare le cellule normali. Attualmente esistono anche convincenti evidenze che mostrano che l’inibizione della premiazione di Ras può non essere necessaria per ottenere gli effetti antineoplastici da parte degli FTI. Infatti, altre proteine famesilate coinvolte nella trasformazione neoplastica, come la proteina RhoB, le fosfatasi PRL-1, 2, 3, rap 2, laminina A e B e le proteine centromeriche CENP-E/CENP-F, possono essere anche importanti target per gli effetti antitumorali degli FTI [a) Pan J, et al. Recent advances in understanding thè antineoplastic mechanisms of famesyltransferase inhibitors. Cancer Res. Since the famesylation process is fundamental in the activity of Ras oncoproteins, specific inhibition of FTase is a potentially effective therapeutic strategy. It would also allow it to act with the functions of cancer cells without affecting normal cells. Currently, there is also convincing evidence showing that inhibition of the Ras award may not be necessary to obtain the antineoplastic effects by the FTI. Indeed, other famesylated proteins involved in neoplastic transformation, such as the RhoB protein, the phosphatases PRL-1, 2, 3, rap 2, laminin A and B and the centromeric proteins CENP-E / CENP-F, may also be important targets for the anticancer effects of FTIs [a) Pan J, et al. Recent advances in understanding the antineoplastic mechanisms of famesyltransferase inhibitors. Cancer Res.
2005; 65: 9109-12. b) Jiang K et al. The phosphoinositide 3-OH-kinase/AKT2 pathway as a criticai target for amesyltransferase inhibitor-induced apoptosis. Mal Celi Biol 2000; 20: 139-148.]. Infatti, è stato osservato che nelle cellule trattate con FTI ha luogo l’accumulo di RhoB geranilgeranilato, il quale induce l’apoptosi delle cellule. [Prendergast, G. C. et al. Famesyltransferase inhibitors: antineoplastic properties, mechanisms of action, and clinical prospects. Semin Cancer Biol, 10: 443-452., 2000]. In altri modelli cellulari, gli FTI inibiscono il pathway della chinasi PI-3. [Pio, I., et al. The phosphoinositide 3-kinase/Alct pathway is activated by daunorubicin in human acute myeloid leukemia celi lines. FEBS Leti, 452 : 150-154., 1999]. Recentemente, abbiamo indagato gli effetti citotossici di vari inibitori della FTasi, incluso Lonafamib (SCH66336), nelle cellule di leucemia mieloide acuta (AML) e cronica (CML). Gli effetti citotossici osservati furono correlati all’aumento dell’apoptosi Inoltre FTI attivarono la caspasi 3 lasciando inalterate le caspasi 1 ed 8 e contribuirono ad innalzare l’espressione dell’mRNA dell’inducibile sintasi dell’ossido nitrico (iNOS) con conseguente innalzamento della produzione di ossido nitrico (NO). Pertanto, concludemmo che gli FTI potevano indurre apoptosi selettiva nelle cellule CML ed AML attraverso l’attivazione di iNOS e caspasi-3 [a) Sederi C. et al. Involvement of nitric oxide in faesyltransferase inhibitor-mediated apoptosis in chronic myeloid leukemia cells. Blood. 2003; 102: 1490-8. b) Sederi C. et al. Famesyltransferase inhibitors induce apoptosis in acute myeloid leukemia cells via activation of inducible nitric oxide synthase and caspase-3 without Fas, BCL-2 and P53 modulation. Haematologica. 2003; 88 (Suppl n.15), 177.]. In conclusione, su 4 molecole inizialmente sviluppate da diverse aziende farmaceutiche (Johnson & Johnson e Schering Ploughs) con l'obiettivo di inibire tra cui Tipifamib (Zamestra®, RI 15777) [a) D.W. End et al., Characterization of thè Ìtitumor effects of thè selective famesyl protein transferase inhibitor RI 15777 in vivo and in vitro, Cancer Res 61 (2001), pp. 131-137. b) A.D. Cox et al. Famesyltransferase inhibitors: promises and realities, Curr Opin Pharmacol 2 (2002), pp. 388-393.] e Lonafamib (Sarasar®, SCH 6336) [a) E.J. Feldman, Famesyltransferase inhibitors in myelodysplastic syndrome, Curr Hematol Rep 4 (2005), pp. 186-190. b)_A.K. Ganguly et al. Famesyl protein transferase inhibition: a novel approach to anti-tumor therapy. thè discovery and development of SCH 66336, Curr Med Chem 8 (2001), pp. 1419-1436.], nessuna ha superato la sperimentazione clinica a causa dei loro effetti avversi e del meccanismo d’azione non chiarito. Pertanto, resta aperto uno spazio di indagine in questo campo nel quale si colloca lo sviluppo dei prodotti di questa invenzione. 2005; 65: 9109-12. b) Jiang K et al. The phosphoinositide 3-OH-kinase / AKT2 pathway as a criti target for amesyltransferase inhibitor-induced apoptosis. Mal Celi Biol 2000; 20: 139-148.]. In fact, it has been observed that in the cells treated with FTI the accumulation of RhoB geranylgeranilate takes place, which induces apoptosis of the cells. [Prendergast, G. C. et al. Famesyltransferase inhibitors: antineoplastic properties, mechanisms of action, and clinical prospects. Semin Cancer Biol, 10: 443-452., 2000]. In other cellular models, FTIs inhibit the PI-3 kinase pathway. [Pio, I., et al. The phosphoinositide 3-kinase / Alct pathway is activated by daunorubicin in human acute myeloid leukemia celi lines. FEBS Leti, 452: 150-154., 1999]. Recently, we investigated the cytotoxic effects of various FTase inhibitors, including Lonafamib (SCH66336), in acute myeloid leukemia (AML) and chronic (CML) cells. The observed cytotoxic effects were correlated to the increase in apoptosis.Furthermore, FTI activated caspase 3 leaving unchanged caspases 1 and 8 and contributed to increase the mRNA expression of inducible nitric oxide synthase (iNOS) with consequent increase in production of nitric oxide (NO). Therefore, we concluded that FTIs could induce selective apoptosis in CML and AML cells through the activation of iNOS and caspase-3 [a) Sederi C. et al. Involvement of nitric oxide in faesyltransferase inhibitor-mediated apoptosis in chronic myeloid leukemia cells. Blood. 2003; 102: 1490-8. b) Sederi C. et al. Famesyltransferase inhibitors induces apoptosis in acute myeloid leukemia cells via activation of inducible nitric oxide synthase and caspase-3 without Fas, BCL-2 and P53 modulation. Haematological. 2003; 88 (Suppl no.15), 177.]. In conclusion, on 4 molecules initially developed by various pharmaceutical companies (Johnson & Johnson and Schering Plows) with the aim of inhibiting including Tipifamib (Zamestra®, RI 15777) [a) D.W. End et al., Characterization of the Ìtitumor effects of the selective famesyl protein transferase inhibitor RI 15777 in vivo and in vitro, Cancer Res 61 (2001), pp. 131-137. b) A.D. Cox et al. Famesyltransferase inhibitors: promises and realities, Curr Opin Pharmacol 2 (2002), pp. 388-393.] And Lonafamib (Sarasar®, SCH 6336) [a) E.J. Feldman, Famesyltransferase inhibitors in myelodysplastic syndrome, Curr Hematol Rep 4 (2005), pp. 186-190. b) _A.K. Ganguly et al. Famesyl protein transferase inhibition: a novel approach to anti-tumor therapy. the discovery and development of SCH 66336, Curr Med Chem 8 (2001), pp. 1419-1436.], None have passed clinical trials due to their adverse effects and the unclear mechanism of action. Therefore, a space of investigation remains open in this field in which the development of the products of this invention takes place.
La presente invenzione ha per oggetto i composti di formule generali (I) e (II) e tutti i loro possibili derivati (vedi Tavola 1 allegata), che inibiscono la prenilazione di Ras. Ri è selezionato dal gruppo che consiste di alchili saturi lineari, ramificati, ciclici e policiclici, insaturi lineari, ramificati, ciclici e policiclici, ed alchilarilici; R2è selezionato dal gruppo che consiste di esteri alchilcarbonilossi, dimetilaminoalchili, arili, alchilarili, arileterocicli, arilarili, ed amminoarili; X è selezionato dal gruppo che consiste di O, S ed NH. The present invention relates to compounds of general formulas (I) and (II) and all their possible derivatives (see attached Table 1), which inhibit Ras prenylation. Ri is selected from the group consisting of linear, branched, cyclic and polycyclic saturated alkyls, linear, branched, cyclic and polycyclic unsaturated alkyls, and alkylaryl; R2 is selected from the group consisting of alkylcarbonyloxy, dimethylaminoalkyl, aryl, alkylaryl, arylheterocycle, arylaryl, and aminoaryl esters; X is selected from the group consisting of O, S and NH.
Come è riportato nei casi specifici, i seguenti termini hanno i significati indicati: As reported in specific cases, the following terms have the meanings indicated:
Il termine “alchile” identifica essenzialmente un gruppo monovalente derivato da una catena idrocarburica satura lineare o ramificata per rimozione di un singolo atomo di idrogeno. The term “alkyl” essentially identifies a monovalent group derived from a linear or branched saturated hydrocarbon chain by removal of a single hydrogen atom.
Il termine “cicloalchilalchile”, usato qui, si riferisce ad un sistema ciclico a sei termini non-aromatico legato a ponte con un ulteriore ciclo sostituito da alchili. The term “cycloalkylalkyl”, used here, refers to a non-aromatic six-membered cyclic system bridged with an additional cycle substituted by alkyls.
termine “alchenile”, usato qui, si riferisce ad un gruppo alchilico, come definito sopra, cntenente uno o più doppi legami carbonio-carbonio. The term "alkenyl", used herein, refers to an alkyl group, as defined above, containing one or more carbon-carbon double bonds.
termine “carbonilossi”, usato qui, si riferisce ad un estere, dove il gruppo alcanoile è legato al raggruppamento molecolare parente mediante un atomo di ossigeno di un gruppo alchilossi. The term "carbonyloxy", used here, refers to an ester, where the alkanoyl group is bonded to the parent molecular grouping by an oxygen atom of an alkyloxy group.
Il termine “amino sostituito”, usato qui, si riferisce sia a mono che a di-sostituiti gruppi amminici. Questi termini, da soli o in combinazione, illustrano un radicale di formula -NR’R”, dove nel caso della monosostituzione uno dei due R è idrogeno e l’altro può essere selezionato fra gli alchili, cicloalchili, arili eterocicli, (aril)alchili, (eterociclo)alchili, eteroarili ed etero(aril)alchili; nel caso della di-sostituzione, R’ ed R” sono indipendentemente selezionati fra alchili, cicloalchili, arili, eterocicli ed, eteroarili. The term "substituted amino", used here, refers to both mono and di-substituted amino groups. These terms, alone or in combination, illustrate a radical of the formula -NR'R ", where in the case of the monosubstitution one of the two Rs is hydrogen and the other can be selected among the alkyls, cycloalkyls, aryl heterocycles, (aryl) alkyls, (heterocycle) alkyls, heteroaryls and hetero (aryl) alkyls; in the case of substitution, R 'and R "are independently selected from alkyls, cycloalkyls, aryls, heterocycles and heteroaryls.
Il termine “arilico”, usato qui, si riferisce ad un sistema monociclico aromatico, fenilico o piridinico, un sistema biciclico o triciclico condensato. Il gruppo arilico di questa invenzione può essere opzionalmente sostituito con uno o più sostituenti selezionati tra gruppi alchilici, alogeni, trifluorometile, nitro, ciano, metossi e un addizionale gruppo fenilico o piridinico. The term "aryl", used herein, refers to an aromatic, phenyl or pyridine monocyclic system, a condensed bicyclic or tricyclic system. The aryl group of this invention can optionally be substituted with one or more substituents selected from alkyl, halogen, trifluoromethyl, nitro, cyano, methoxy groups and an additional phenyl or pyridine group.
Il termine “alogeno”, usato qui, rappresenta fluoro, clóro, bromo e iodio. The term “halogen”, used here, represents fluorine, chlorine, bromine and iodine.
Il termine “(aril)alchilico”, usato qui, si riferisce ad un gruppo arilico legato al raggruppamento molecolare parente attraverso un gruppo alchilico, come definito sopra. Il termine “eterociclo”, usato qui, si riferisce ad un anello a cinque ed a sei termini contenente uno, due o tre eteroatomi (azoto, ossigeno e zolfo). Esempi rappresentativi di eterocicli includono morfolina, piperidina, piperazina e metilpiperazina. I gruppi eterociclici della presente invenzione possono sostituire un idrogeno su un atomo di carbonio del gruppo fenilico legato al raggruppamento molecolare parente. The term "(aryl) alkyl", used herein, refers to an aryl group bonded to the parent molecular grouping through an alkyl group, as defined above. The term "heterocycle", used here, refers to a five- and six-membered ring containing one, two or three heteroatoms (nitrogen, oxygen and sulfur). Representative examples of heterocycles include morpholine, piperidine, piperazine and methylpiperazine. The heterocyclic groups of the present invention can replace a hydrogen on a carbon atom of the phenyl group bonded to the parent molecular grouping.
Il termine “fenilaminico”, usato qui, si riferisce ad un gruppo fenilico legato al raggruppamento molecolare parente attraverso un gruppo amminico secondario (idrazina). Il gruppo fenilico di questa invenzione può essere opzionalmente sostituito con uno o più sostituenti selezionati tra gruppi alchilici, alogeni, trifluorometile, nitro, ciano e metossi. Come inibitori della prenilazione di Ras, questi composti sono utili nel trattamento di tumori solidi primari e metastatici come carcinoma della mammella, colon, retto, polmone; orofaringe; ipofaringe, esofago, stomaco, pancreas, fegato, cistifellea, dotti biliari; piccolo intestino; del tratto urinario (reni, vescica, e uretere); genitale femminile (cervice uterina, utero e ovaie); tratto genitale maschile (prostata, vescicole seminali, e testicoli); ghiandole endocrine (tiroide, surrene, e ghiandola pituitaria); pelle (emangiomi, melanomi e sarcomi), tumori del cervello, nervi, ed occhi; meningi (astrocitomi, gliomi, glioblastomi, retinoblastomi, neuromi, neuroblastomi, meningiomi); tumori solidi derivanti da neoplasie ematopoietiche (leucemie e cloromi); plasmacitomi; placche; tumori di micosi fungoidi; linfomi/leucemie cutanee di cellule T, linfomi di Hodgkin, compresi i linfomi non-Hodgkin; profilassi di malattie autoimmuni (artrite reumatoide, artrite degenerativa e immunitaria); malattie oculari (retinopatia diabetica, retinopatia di prematurità, rigetto del trapianto di cornea, fìbroplasia retrolentale, glaucoma neovascolare, rubeosi, neovascolarizzazione della retina a causa di degenerazione maculare, ed ipossia), malattie della pelle (psoriasi, emagiomi e proliferazione capillare nelle placche aterosclerotiche). In base ai metodi di trattamento, i composti della presente invenzione possono essere utili anche per la prevenzione di metastasi tumorali, se usati da soli o in combinazione con radioterapia e/o altri trattamenti chemioterapici convenzionali somministrati ai pazienti per il trattamento del cancro. Quando si utilizzano i composti della presente invenzione per la chemioterapia, la dose efficace terapeutica specifica per ogni paziente dipenderà da fattori quali la malattia in trattamento e la gravità della malattia; l'attività del particolare composto lato ; la composizione specifica usata; l'età, il peso corporeo, la salute in generale, il sesso, e la dieta del paziente, il tempo di somministrazione, la via di somministrazione; la velocità di escrezione del composto usato; la durata del trattamento; e i farmaci utilizzati in combinazione con o contemporaneamente con i composti utilizzati. Ad esempio, quando un composto della presente invenzione viene utilizzato nel trattamento di tumori solidi, esso può essere somministrato con agenti chemioterapici, quali alfa inteferon, COMP (ciclofosfamide, vincristina, metotressato, e prednisone), etoposide, mBACOD (metortressato, bleomicina, doxorubicina, ciclofosfamide, vincristina e desametasone), PRO-MACE/MOPP (prednisone, metotressato, doxorubicina, ciclofosfamide, taxolo, etoposide/mecloretamina, vincristina, prednisone e procarbazina), vincristina, vinblastina, angioinibine, TNP-470, pentosan polisolfato, fattore piastrinico 4, angiostatina, LM-609, SU-101, CM-101, Tecgalan, talidomide, SP-PG, e simili. Ad esempio, un tumore può essere trattato convenzionalmente mediante chirurgia, radiazioni o chemioterapia ed, in aggiunta, con un composto della presente invenzione per estendere la dormienza delle micrometastasi, stabilizzare ed inibire la crescita di qualsiasi residuo del tumore primario. I composti della presente invenzione possono essere somministrati per via orale, parenterale, osmotica (spray nasale), rettale, vaginale, o topica per formulazioni contenenti camers, coadiuvanti, diluenti, veicoli, o una loro combinazione. Il termine "parenterale" comprende l'infusione e l’iniezione sottocutanea, endovenosa, intramuscolare, ed intrastemale. The term “phenylamine”, used here, refers to a phenyl group linked to the parent molecular grouping through a secondary amino group (hydrazine). The phenyl group of this invention can optionally be substituted with one or more substituents selected from alkyl, halogen, trifluoromethyl, nitro, cyano and methoxy groups. As inhibitors of Ras prenylation, these compounds are useful in the treatment of primary and metastatic solid tumors such as breast, colon, rectum, lung carcinoma; oropharynx; hypopharynx, esophagus, stomach, pancreas, liver, gallbladder, bile ducts; small intestine; urinary tract (kidneys, bladder, and ureter); female genital (cervix, uterus and ovaries); male genital tract (prostate, seminal vesicles, and testes); endocrine glands (thyroid, adrenal, and pituitary gland); skin (hemangiomas, melanomas and sarcomas), tumors of the brain, nerves, and eyes; meninges (astrocytomas, gliomas, glioblastomas, retinoblastomas, neuromas, neuroblastomas, meningiomas); solid tumors resulting from hematopoietic neoplasms (leukemias and chloromas); plasmacytomas; plaques; mycosis fungoides tumors; cutaneous T-cell lymphomas / leukemias, Hodgkin's lymphomas, including non-Hodgkin's lymphomas; prophylaxis of autoimmune diseases (rheumatoid arthritis, degenerative and immune arthritis); eye diseases (diabetic retinopathy, prematurity retinopathy, corneal transplant rejection, retrolental phybroplasia, neovascular glaucoma, rubeosis, neovascularization of the retina due to macular degeneration, and hypoxia), skin diseases (psoriasis, hemagiomas and proliferation of atherosclerotic plaques ). Based on the treatment methods, the compounds of the present invention may also be useful for the prevention of tumor metastases, when used alone or in combination with radiotherapy and / or other conventional chemotherapy treatments administered to patients for cancer treatment. When the compounds of the present invention are used for chemotherapy, the specific therapeutic effective dose for each patient will depend on factors such as the disease being treated and the severity of the disease; the activity of the particular compound side; the specific composition used; the patient's age, body weight, general health, sex, and diet, time of administration, route of administration; the rate of excretion of the compound used; the duration of the treatment; and drugs used in combination with or simultaneously with the compounds used. For example, when a compound of the present invention is used in the treatment of solid tumors, it can be administered with chemotherapeutic agents, such as alpha inteferon, COMP (cyclophosphamide, vincristine, methotrexate, and prednisone), etoposide, mBACOD (metortressate, bleomycin, doxorubicin) , cyclophosphamide, vincristine and dexamethasone), PRO-MACE / MOPP (prednisone, methotrexate, doxorubicin, cyclophosphamide, taxol, etoposide / mechloretamine, vincristine, prednisone and procarbazine), vincristine, vinblastine, angioinibine, pentane, TNP-sulfate 4, angiostatin, LM-609, SU-101, CM-101, Tecgalan, thalidomide, SP-PG, and the like. For example, a tumor can be conventionally treated by surgery, radiation or chemotherapy and, in addition, with a compound of the present invention to extend the dormancy of micrometastases, stabilize and inhibit the growth of any residue of the primary tumor. The compounds of the present invention can be administered orally, parenteral, osmotic (nasal spray), rectal, vaginal, or topically for formulations containing camers, adjuvants, diluents, vehicles, or a combination thereof. The term "parenteral" includes subcutaneous, intravenous, intramuscular, and intrastemal infusion and injection.
Sospensioni acquose o oleose dei composti della presente invenzione somministrate per via parenterale possono essere formulate con agenti di dispersione, bagnanti o di sospensione. La preparazione iniettabile può essere anche una soluzione iniettabile o sospensione in un diluente o solvente. Tra diluenti o solventi accettabili utilizzati vi sono acqua, soluzione fisiologica, soluzione di Ringer, tamponi, acidi diluiti e basi, soluzioni diluite di aminoacidi, monogliceridi, digliceridi, acidi grassi come l’acido oleico, e oli fissi c monogliceridi o digliceridi. Aqueous or oily suspensions of the compounds of the present invention administered parenterally can be formulated with dispersing, wetting or suspending agents. The injectable preparation can also be a solution for injection or suspension in a diluent or solvent. Acceptable diluents or solvents used include water, physiological solution, Ringer's solution, buffers, diluted acids and bases, dilute solutions of amino acids, monoglycerides, diglycerides, fatty acids such as oleic acid, and fixed oils and monoglycerides or diglycerides.
L'effetto chemioterapeutico di composti somministrati per via parenterale può essere prolungato rallentando il loro assorbimento. Un modo per rallentare l'assorbimento di un particolare composto è la somministrazione forme depot iniettabili comprendenti sospensioni di forme del composto cristallino, amorfo, o insolubile in acqua. Il tasso di assorbimento del composto dipende dalla sua velocità di dissoluzione, che è, a sua volta, dipendente dal suo stato fisico. Un altro modo per rallentare l'assorbimento di un particolare composto è la somministrazione di forme depot iniettabili comprendenti il composto come soluzione oleosa o in sospensione. Ancora un altro modo per rallentare l'assorbimento di un particolare composto è la somministrazione di forme depot iniettabili comprendenti matrici di microcapsule del composto intrappolato all'interno di liposomi, microemulsioni, o polimeri biodegradabili come polilattide-poliglicolide, poliortoesteri o polianidridi. A seconda del rapporto del farmaco con il polimero e la composizione del polimero, il tasso di rilascio di farmaco può essere controllato. The chemotherapeutic effect of parenterally administered compounds can be prolonged by slowing their absorption. One way to slow the absorption of a particular compound is by administering injectable depot forms comprising suspensions of crystalline, amorphous, or water-insoluble forms of the compound. The absorption rate of the compound depends on its dissolution rate, which is, in turn, dependent on its physical state. Another way to slow the absorption of a particular compound is by administering injectable depot forms comprising the compound as an oily solution or in suspension. Yet another way to slow the absorption of a particular compound is the administration of injectable depot forms comprising microcapsule arrays of the compound trapped within liposomes, microemulsions, or biodegradable polymers such as polylactide-polyglycolide, polyorthoesters or polyanhydrides. Depending on the relationship of the drug to the polymer and the composition of the polymer, the drug release rate can be controlled.
Anche i cerotti transdermici consentono la distribuzione controllata dei composti. Il tasso di assorbimento può essere rallentato usando membrane che controllano la velocità o catturando il composto in una matrice polimerica o gel. Al contrario, possono essere utilizzati promotori dell’assorbimento, i cosiddetti enhancers, per aumentare l'assorbimento. Transdermal patches also allow for controlled distribution of compounds. The rate of absorption can be slowed by using membranes that control the rate or by capturing the compound in a polymer or gel matrix. On the contrary, absorption promoters, the so-called enhancers, can be used to increase absorption.
Le forme solide per la somministrazione orale comprendono capsule, compresse, pillole, polveri e granuli. In queste forme solide, il composto attivo può opzionalmente comprendere diluenti come saccarosio, lattosio, amido, talco, acido silicico, idrossido di alluminio, silicati di calcio, polvere di poliammide, lubrificanti ed eccipienti come magnesio stearato o cellulosa microcristallina. Capsule, compresse e pillole possono comprendere anche agenti alcalini e compresse e pillole possono essere preparati con rivestimenti enterici o altri rivestimenti che controllano il rilascio. Polveri e spray possono anche contenere eccipienti come talco, acido silicico, idrossido di alluminio, silicato di co, poliammide in polvere, o loro miscele. Gli sprays possono inoltre contenere propellenti come clorofluoroidrocarboni o succedanei. Solid forms for oral administration include capsules, tablets, pills, powders and granules. In these solid forms, the active compound can optionally comprise diluents such as sucrose, lactose, starch, talc, silicic acid, aluminum hydroxide, calcium silicates, polyamide powder, lubricants and excipients such as magnesium stearate or microcrystalline cellulose. Capsules, tablets and pills can also comprise alkaline agents and tablets and pills can be prepared with enteric or other release-controlling coatings. Powders and sprays may also contain excipients such as talc, silicic acid, aluminum hydroxide, co silicate, powdered polyamide, or mixtures thereof. The sprays may also contain propellants such as chlorofluorohydrocarbons or substitutes.
Forme liquide di dosaggio per la somministrazione orale includono emulsioni, microemulsioni, soluzioni, sospensioni, sciroppi, elisir comprendenti diluenti inerti come l'acqua. Queste composizioni possono comprendere anche coadiuvanti come bagnanti, emulsionanti, sospensioni, dolcificanti ed aromi. Liquid dosage forms for oral administration include emulsions, microemulsions, solutions, suspensions, syrups, elixirs including inert diluents such as water. These compositions can also comprise adjuvants such as wetting agents, emulsifiers, suspensions, sweeteners and flavorings.
Forme di dosaggio topiche comprendono unguenti, paste, creme, lozioni, gel, polveri, soluzioni, spray, inalanti, e cerotti transdermici. Il composto viene miscelato in ambiente sterile con un vettore e gli eventuali tamponi e conservanti necessari. Queste forme di dosaggio possono includere anche eccipienti, come grassi animali e vegetali, oli, cere, paraffine, amido, tragacanth, derivati della cellulosa, polietilene glicoli, siliconi, bentoniti, idrotalciti, acido silicico, talco e ossido di zinco, o loro miscele. Supposte per somministrazione rettale o vaginale possono essere preparate mescolando i composti della presente invenzione con un opportuno eccipiente non irritante come burro di cacao o polietilene glicole, ciascuno dei quali è solido a temperatura ordinaria, ma fluido in vagina o nel retto. Formulazioni oftalmiche comprendenti colliri, pomate oftalmiche, polveri, e soluzioni sono anche contemplate nello scopo della presente invenzione. Topical dosage forms include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, and transdermal patches. The compound is mixed in a sterile environment with a carrier and any necessary buffers and preservatives. These dosage forms may also include excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, hydrotalcites, silicic acid, talc and zinc oxide, or mixtures thereof. . Suppositories for rectal or vaginal administration can be prepared by mixing the compounds of the present invention with a suitable non-irritating excipient such as cocoa butter or polyethylene glycol, each of which is solid at ordinary temperature, but fluid in the vagina or rectum. Ophthalmic formulations including eye drops, eye ointments, powders, and solutions are also contemplated within the scope of the present invention.
La dose giornaliera totale dei composti della presente invenzione somministrata ad un paziente in dose singola o dosi suddivise può essere in quantità compresa tra circa 0,1 e circa 200 mg/kg di peso corporeo o, preferibilmente, tra circa 0,25 e circa 100 mg/kg di peso corporeo. The total daily dose of the compounds of the present invention administered to a patient in single or divided doses can be in an amount ranging from about 0.1 to about 200 mg / kg of body weight or, preferably, from about 0.25 to about 100. mg / kg of body weight.
I composti riportati in questa invenzione sono stati testati per l’attività antiproliferativa su due linee cellulari leucemiche, K562 ( human erythroid leukemia celi line ) e KGla (human myeloid celi line), secondo il Celi Titer Aqueous One Solution Proliferation Assay Promega, Madison, WI), un metodo colorimetrico che consente di determinare il numero di cellule vitali in saggi di proliferazione. Il metodo prevede l’uso di [3-(4,5-dimetiltiazol-2-il)-5-(3-carbossimetossifenil)-2-(4-sulfofenil)-2H-tetrazolo] (MTS) e di fenazina etosolfato (PES), un reagente ad accoppiamento elettronico. L’MTS viene ridotto dalle cellule in un prodotto colorato, solubile nel mezzo di coltura cellulare. Tale riduzione è mediata da NADPH o NADH prodotti dagli enzimi deidrogenasi in cellule metabolicamente attive. Il saggio è eseguito aggiungendo una piccola quantità di Celi Titer Aqueous One Solution Reagent direttamente alle piastre cellulari, incubando per 2 ore (37 °C, 5% C02) e poi leggendo l’assorbanza a 490 nm ad un lettore ELISA. Il valore di densità ottica (O.D.) letto è direttamente proporzionale al numero di cellule vive presenti sulla piastra. Il valore di O.D. del campione non trattato (campione a cui non è stato aggiunto nessun IFT) rappresenta il 100% di proliferazione. Quindi, si calcola il rapporto tra il valore di O.D. dei vari campioni ed il valore di O.D. del 100% di proliferazione per ottenere la misura della riduzione della proliferazione di ogni campione rispetto al 100% di proliferazione. The compounds reported in this invention were tested for antiproliferative activity on two leukemic cell lines, K562 (human erythroid leukemia celi line) and KGla (human myeloid celi line), according to the Celi Titer Aqueous One Solution Proliferation Assay Promega, Madison, WI), a colorimetric method that allows to determine the number of viable cells in proliferation assays. The method involves the use of [3- (4,5-dimethylthiazol-2-yl) -5- (3-carboxymethoxyphenyl) -2- (4-sulfophenyl) -2H-tetrazole] (MTS) and phenazine ethosulfate ( PES), an electronically coupled reagent. MTS is reduced by the cells into a colored product, soluble in the cell culture medium. This reduction is mediated by NADPH or NADH produced by dehydrogenase enzymes in metabolically active cells. The assay is performed by adding a small amount of Celi Titer Aqueous One Solution Reagent directly to the cell plates, incubating for 2 hours (37 ° C, 5% C02) and then reading the absorbance at 490 nm to an ELISA reader. The optical density (O.D.) value read is directly proportional to the number of live cells present on the plate. The value of O.D. of the untreated sample (sample to which no IFT has been added) represents 100% proliferation. Then, the ratio of the O.D. of the various samples and the O.D. 100% proliferation to obtain the measure of the proliferation reduction of each sample compared to 100% proliferation.
L'ffetto di alcuni composti rappresentativi della presente invenzione, misurato come percentuale di inibizione della vitalità cellulare, è riportato in Tabella 1 (vedi Tavola 1 allegata). The effect of some representative compounds of the present invention, measured as a percentage of inhibition of cell viability, is reported in Table 1 (see attached Table 1).
L’effetto antiproliferativo degli esempi 1 e 2 sulle linee cellulari K562 e KG la potrebbe essere dovuto all’induzione di apoptosi. L’analisi di DNA a basso peso molecolare estratto dalle cellule KGla e K562 fatte crescere in presenza degli esempi 1 e 2 ha mostrato una degradazione del DNA nucleosomale rilevato mediante elettroforesi su gel di agarosio carat dell’apoptosi. La citometria a flusso sul DNA proveniente dalle cellule KG la esposte a 1 e 2, eseguita mediante colorazione con ioduro di propidio (PI) ed essina V (AnnV), ha confermato che questi composti innalzano fortemente l’apoptosi delle cellule KGla e K562, come illustrato in Tabella 2 (vedi Tavola 1 allegata). The antiproliferative effect of examples 1 and 2 on the K562 and KG la cell lines could be due to the induction of apoptosis. The analysis of low molecular weight DNA extracted from KGla and K562 cells grown in the presence of examples 1 and 2 showed a degradation of the nucleosomal DNA detected by electrophoresis on apoptosis carat agarose gel. Flow cytometry on DNA from KG cells exposed to 1 and 2, performed by staining with propidium iodide (PI) and essin V (AnnV), confirmed that these compounds strongly increase the apoptosis of KGla and K562 cells. as illustrated in Table 2 (see Table 1 attached).
La traslocazione dell’antigene lipidico fosfatidilserìna sul lato esterno della membrana plasmatica rappresenta un evento precoce dell'apoptosi e si manifesta quando la cellula conserva ancora la sua integrità cellulare. L’annexina V (AnnV) è una proteina che presenta un'alta affinità per la fosfatidilserìna e viene quindi utilizzata come probe per iconoscere queste cellule. L’uso di questa proteina ci permette di riconoscere Tapoptosi ad uno stadio più precoce. Altri metodi sono basati su variazioni più tardive della cellula, ad esempio a livello nucleare, con la frammentazione di DNA. L'esposizione all'esterno della fosfatidilserìna non è un evento esclusivo dell'apoptosi, ma anche di un' altra forma di morte cellulare, la necrosi, dove le cellule hanno perso la loro integrità cellulare e sono diventate permeabili a coloranti vitali come lo ioduro di propidio (PI). L'uso combinato di annexina V coniugata al fluorocromo FITC (fluoresceinisotiocianato) e ioduro di propidio ci permette, in citofluorimetria, di discriminare tra cellule in apoptosi allo stadio iniziale (AnnV+/PI-), cellule in necrosi o apoptosi allo stadio finale (AnnV+/PI+) e cellule vive (AnnV-/PI-). Le percentuali indicate in Tabella 2 (vedi Tavola 1 allegata) si riferiscono alla prima popolazione calcolata sul totale degli eventi cellulari acquisiti. The translocation of the phosphatidyl serine lipid antigen on the outer side of the plasma membrane represents an early event of apoptosis and occurs when the cell still retains its cellular integrity. Annexin V (AnnV) is a protein that has a high affinity for phosphatidylserine and is therefore used as a probe to recognize these cells. The use of this protein allows us to recognize Tapoptosis at an earlier stage. Other methods are based on later variations of the cell, for example at the nuclear level, with the fragmentation of DNA. Exposure to the outside of phosphatidyl serine is not an exclusive event of apoptosis, but also of another form of cell death, necrosis, where cells have lost their cellular integrity and have become permeable to vital dyes such as iodide. of propidium (PI). The combined use of annexin V conjugated to fluoresceinisothiocyanate (fluoresceinisothiocyanate) and propidium iodide allows us, in flow cytometry, to discriminate between cells in early stage apoptosis (AnnV + / PI-), cells in necrosis or end stage apoptosis (AnnV + / PI +) and live cells (AnnV- / PI-). The percentages indicated in Table 2 (see Table 1 attached) refer to the first population calculated on the total number of cellular events acquired.
Gli esempi 1 e 2 sono stati testati con la metodologia sopra riportata anche su cellule mononucleari del midollo osseo (BMMNC) di sei leucemie mieloidi acute oltre che su quelle di un donatore sano. Come illustrato nella Figura 1 (vedi Tavola 1 allegata), gli esempi 1 e 2 mostrano di non inibire la proliferazione delle cellule normali, ad una concentrazione inferiore a 10<-4>, mentre inibiscono fortemente la proliferazione delle cellule cancerose. Examples 1 and 2 were tested with the above methodology also on bone marrow mononuclear cells (BMMNC) of six acute myeloid leukemias as well as on those of a healthy donor. As illustrated in Figure 1 (see attached Table 1), examples 1 and 2 show that they do not inhibit the proliferation of normal cells, at a concentration below 10 <-4>, while strongly inhibit the proliferation of cancerous cells.
Sulla base dei risultati ottenuti dai riportati esperimenti, sono stati selezionati i tempi e le concentrazioni opportune degli esempi 1 e 2 ai quali effettuare i saggi di determinazione ell’attività di Ras. A tale scopo è stato utilizzato il Ras activation assay (Upstate), che utilizza il metodo Pull-Down, una tecnica che consente di verificare l'interazione fra due proteine. Si utilizza una proteina con un tag (ad es. GST, His6, biotina, etc.) detta bait (esca) per legare e “tirare giù” (“pull-down”) una proteina partner (prey = preda), che è uella di cui si vuole verificare l’interazione con la proteina esca. In questo caso la proteina utilizzata come esca è il dominio di Raf-1 in grado di legare Ras. La proteina Raf-1 presenta un tag di GST (glutatione S-transferasi) ed è legata ad una resina (glutatione agarosio). Le cellule K562 sono state incubate con gli esempi selezionati (1 e 2) alle concentrazioni che avevano dato i migliori risultati nel saggio di proliferazione. A 48 ore le cellule sono state raccolte e Usate. Il Usato cellulare è stato quindi incubato con la proteina esca (Raf-1) per 45 minuti in agitazione lenta, per consentire alla proteina preda (Ras) di legarsi alla proteina esca. I complessi “proteina esca-proteina preda” che si sono formati sono stati recuperati e analizzati mediante elettroforesi su gel di poliacrilammide (SDS-PAGE) . Dopo la corsa elettroforetica le proteine sono state trasferite su una membrana di polivinildenfluoruro (PVDF), incubata successivamente con un anticorpo primario AntiRas (over night). Il giorno successivo, la membrana è stata incubata con un anticorpo secondario, diretto contro l’anticorpo primario e coniugato ad una perossidasi. La membrana è stata quindi bagnata con un reagente contenente luminolo che consente la detection. La perossidasi (legata al complesso anticorpo primario-anticorpo secondario) causa l’ossidazione del luminolo con conseguente emissione di luce, che va ad impressionare una lastra autoradiografica, formando delle bande. Le 2 bande indicate sulla lastra in Figura 2 (vedi Tavola 1 allegata) rappresentano Ras attivata, mentre NT è il campione non trattato. I campioni con gli esempi 1 (ΚΓ<6>M) e 2 (IO<'12>M) mostrano una forte inibizione dell’attività di Ras. On the basis of the results obtained from the above experiments, the appropriate times and concentrations of examples 1 and 2 were selected to carry out the assays for determining the activity of Ras. For this purpose the Ras activation assay (Upstate) was used, which uses the Pull-Down method, a technique that allows to verify the interaction between two proteins. A protein with a tag (eg GST, His6, biotin, etc.) called bait (bait) is used to bind and "pull-down" a partner protein (prey = prey), which is the one whose interaction with the bait protein is to be verified. In this case the protein used as bait is the Raf-1 domain capable of binding Ras. The Raf-1 protein has a GST tag (glutathione S-transferase) and is bound to a resin (glutathione agarose). K562 cells were incubated with the selected examples (1 and 2) at the concentrations which gave the best results in the proliferation assay. At 48 hours the cells were collected and used. The cellular used was then incubated with the bait protein (Raf-1) for 45 minutes under slow agitation, to allow the prey protein (Ras) to bind to the bait protein. The “bait protein-prey protein” complexes that formed were recovered and analyzed by polyacrylamide gel electrophoresis (SDS-PAGE). After the electrophoretic run, the proteins were transferred onto a polyvinyldenfluoride (PVDF) membrane, subsequently incubated with a primary AntiRas antibody (over night). The next day, the membrane was incubated with a secondary antibody, directed against the primary antibody and conjugated to a peroxidase. The membrane was then wetted with a luminol-containing reagent that allows detection. Peroxidase (linked to the primary antibody-secondary antibody complex) causes the oxidation of luminol with consequent emission of light, which impresses an autoradiographic plate, forming bands. The 2 bands indicated on the plate in Figure 2 (see Table 1 attached) represent activated Ras, while NT is the untreated sample. The samples with examples 1 (ΚΓ <6> M) and 2 (10 <'12> M) show a strong inhibition of Ras activity.
I composti della presente invenzione possono essere di fonte commerciale o preparati Attraverso metodi riportati in letteratura e ben noti all’esperto del ramo. Un metodo alternativo di sintesi dei composti di formula generale (I) e (II) (vedi Tavola 1 allegata) è stato realizzato nella presente invenzione allo scopo di facilitare la procedura sintetica e migliorare le rese di reazione (vedi schema 1 e 2 nella Tavola 2 allegata). Lo Schema 1 mostra la sintesi alternativa dei composti di formula (I). II composto di formula (1) è trattato con il furano (4), in soluzione organica per fornire il composto di formula (5) attraversounareazione di Dies-Alder. Esempi di solventi usati in questa reazione includono Acetone, Benzene, Toluene ed Etere etilico. La reazione è condotta a temperatura variabile tra 50 e 25 °C per un tempo che va da 6 ore a tre giorni. Il composto di formula (5) viene fatto reagire con opportune animine, composti di formula (2), per fornire i composti di formula (8). Esempi di solventi usati in questa reazione includono Benzene, Toluene, Etere etilico ed acetone. La reazione è condotta a temperatura variabile tra 50 e 25 °C per un tempo che va da 6 ore a tre giorni. I composti di formula (8) possono essere convertiti ai composti di formula (9) per disidratazione con anidride acetica e neutralizzazione con acetato di sodio. La reazione è di solito condotta a circa 50 °C per 2 ore. I composti di formula (9) possono essere convertiti nei composti di formula (I) per riscaldamento in Toluene a riflusso attraverso una reazione di retro Dies-Alder. Lo Schema 2 mostra una sintesi alternativa per alcuni dei composti di formula (II). I composti di formula (10) possono essere trattati con opportuni eterocicli, composti di formula (4) (dove X = O, NH, S), in soluzione organica per fornire i composti di formula (11) attraverso una reazione di Dies-Alder. Esempi di solventi usati in questa reazione includono Benzene, Toluene ed Etere etilico. La reazione è condotta a temperatura variabile tra 80 e 25 °C per un tempo che va da 6 ore a tre giorni. I composti di formula (11) possono essere fatti reagire con opportuni alchilcloruri, composti di formula (12), in presenza di basi, per i composti di formula (II). Esempi di solventi usati in questa reazione includono e, Toluene, Etere etilico ed acetone. La reazione è condotta a temperatura variabile 25 °C per un tempo che va da 6 ore a tre giorni, The compounds of the present invention can be from commercial sources or prepared through methods reported in the literature and well known to those skilled in the art. An alternative synthesis method of the compounds of general formula (I) and (II) (see attached Table 1) has been implemented in the present invention in order to facilitate the synthetic procedure and improve the reaction yields (see diagram 1 and 2 in Table 2 attached). Scheme 1 shows the alternative synthesis of the compounds of formula (I). The compound of formula (1) is treated with furan (4), in organic solution to provide the compound of formula (5) through a Dies-Alder reaction. Examples of solvents used in this reaction include acetone, benzene, toluene and ethyl ether. The reaction is carried out at a variable temperature between 50 and 25 ° C for a time ranging from 6 hours to three days. The compound of formula (5) is reacted with suitable animins, compounds of formula (2), to provide the compounds of formula (8). Examples of solvents used in this reaction include Benzene, Toluene, Ethyl ether and acetone. The reaction is carried out at a variable temperature between 50 and 25 ° C for a time ranging from 6 hours to three days. The compounds of formula (8) can be converted to the compounds of formula (9) by dehydration with acetic anhydride and neutralization with sodium acetate. The reaction is usually carried out at about 50 ° C for 2 hours. The compounds of formula (9) can be converted into the compounds of formula (I) by heating in Toluene at reflux through a retro Dies-Alder reaction. Scheme 2 shows an alternative synthesis for some of the compounds of formula (II). The compounds of formula (10) can be treated with suitable heterocycles, compounds of formula (4) (where X = O, NH, S), in organic solution to provide the compounds of formula (11) through a Dies-Alder reaction . Examples of solvents used in this reaction include Benzene, Toluene and Ethyl Ether. The reaction is carried out at a variable temperature between 80 and 25 ° C for a time ranging from 6 hours to three days. The compounds of formula (11) can be reacted with suitable alkyl chlorides, compounds of formula (12), in the presence of bases, for the compounds of formula (II). Examples of solvents used in this reaction include e, Toluene, ethyl ether and acetone. The reaction is carried out at a variable temperature of 25 ° C for a time ranging from 6 hours to three days,
presente invenzione verrà ora descritta insieme con alcune realizzazioni che non ne limitano lo scopo. Invece, la presente invenzione copre tutte le alternative, le modifiche e somiglianze che possono essere comprese nella finalità di queste rivendicazioni. Così, i seguenti Esempi, che includono le migliori realizzazioni, illustreranno la migliore pratica della presente invenzione, tenendo presente che gli Esempi hanno lo scopo di illustrare certe particolari realizzazioni e di fornire ciò che si pensa sia la più utile e facilmente coensibile descrizione delle procedure e degli aspetti concettuali. I composti dell’invenzione sono stati nominati utilizzando ChemBioDraw Ultra versione 11.0 (sviluppato da CambridgeSoft, Cambridge CB5 8LA UK). Gli spettri 1H-NMR sono stati registrati con un Bruker-500 spectrometer, mentre gli spettri di massa sono stati ottenuti usando un EI a 70 eV su un ZAB 2F spectrometer, e sono qui sotto riportati per illustrare ulteriormente gli Esempi dell’invenzione. the present invention will now be described together with some embodiments which do not limit its scope. Instead, the present invention covers all alternatives, modifications and similarities which may be encompassed within the scope of these claims. Thus, the following Examples, which include best embodiments, will illustrate the best practice of the present invention, bearing in mind that the Examples are intended to illustrate certain particular embodiments and to provide what is thought to be the most useful and easily co-sensible description of the procedures. and conceptual aspects. The compounds of the invention were named using ChemBioDraw Ultra version 11.0 (developed by CambridgeSoft, Cambridge CB5 8LA UK). The 1H-NMR spectra were recorded with a Bruker-500 spectrometer, while the mass spectra were obtained using an EI at 70 eV on a ZAB 2F spectrometer, and are reported below to further illustrate the Examples of the invention.
ESEMPIO 1 EXAMPLE 1
1 -(( 1 R,2S,3 S,5 S)-2,6,6-trimetilbiciclo[3.1.1 ]eptan-3 -il)- 1 H-pirrolo-2,5-dione Ad una soluzione di anidride maleica (1 mmol) in benzene (10 mi) si aggiunge goccia a goccia una soluzione di furano (1 mmol) in benzene (10 mi) a temperatura ambiente sotto agitazione per tre giorni. La miscela viene portata a secco, a 25 °C e a pressione ridotta, e il residuo lavato con etere etilico. Il solido bianco separato per filtrazione viene dissolto in acetone e addizionato goccia a goccia di una soluzione di (lR,2S,3S,5S)-2,6,6-trimetilbiciclo[3.1.1]eptan-3-ammina (Immole in 5 mi di acetone) sotto agitazione. Dopo 24 ore, la soluzione viene portata a secco sotto vuoto a pressione ridotta ed il solido grezzo dissolto in 10 mi di anidride acetica. La soluzione agitata per 2 ore, diluita con acqua, estratta con toluene e riscaldata a riflusso per 2 ore, fornisce il composto grezzo L<,>Esempio 1 che viene purificato per cromatografia su gel di silice (TLC o colonna eluee cloroformio-metanolo 80:20 w). Resa 75 %. MS (EI) m/z 233; ’H NMR (CDCI3) 2H, s), 3.58 (IH, dd), 2.24 (IH, m), 1,67-1,53 (2H, m), 1.49 (IH, m), 1,24 (IH, m), ,43 (2H, m), 1,02 (6H, s). Anal. Cale. Ci4H19N02, C, 72.07; H, 8.21; N, 6.00; Trovato C, 72.12; H, 8.19; N, 6.04. 1 - ((1 R, 2S, 3 S, 5 S) -2,6,6-trimethylbicyclo [3.1.1] heptan-3 -yl) - 1 H-pyrrole-2,5-dione To an anhydride solution maleic (1 mmol) in benzene (10 ml) a solution of furan (1 mmol) in benzene (10 ml) is added dropwise at room temperature under stirring for three days. The mixture is brought to dryness, at 25 ° C and under reduced pressure, and the residue washed with ethyl ether. The white solid separated by filtration is dissolved in acetone and added dropwise with a solution of (1R, 2S, 3S, 5S) -2,6,6-trimethylbicycle [3.1.1] heptan-3-amine (Immole in 5 ml of acetone) under stirring. After 24 hours, the solution is brought to dryness under vacuum at reduced pressure and the crude solid dissolved in 10 ml of acetic anhydride. The solution stirred for 2 hours, diluted with water, extracted with toluene and heated under reflux for 2 hours, gives the crude compound L <,> Example 1 which is purified by chromatography on silica gel (TLC or column eluee chloroform-methanol 80 : 20 w). Yield 75%. MS (EI) m / z 233; 'H NMR (CDCI3) 2H, s), 3.58 (1H, dd), 2.24 (1H, m), 1.67-1.53 (2H, m), 1.49 (1H, m), 1.24 (1H , m),, 43 (2H, m), 1.02 (6H, s). Anal. Cale. Cl4H19N02, C, 72.07; H, 8.21; N, 6.00; Found C, 72.12; H, 8.19; N, 6.04.
ESEMPIO 2 EXAMPLE 2
2-(4-morpholin-4-ylphenyl)-3a,4,7,7a-tetrahydro-l/7-4,7-epoxyisoindole-l,3-dione Ad una soluzione di maleimmide (1 mmol) in benzene (10 mi) si aggiunge goccia a goccia una soluzione di furano (1 mmol) in benzene (10 mi) a temperatura ambiente sotto agitazione per tre giorni. La miscela viene portata a secco, a 25°C e a pressione ridotta, e il residuo lavato con etere etilico. Il solido bianco separato per filtrazione viene dissolto in acetone e addizionato goccia a goccia di una soluzione di 4-(4-clorofenil)morfolina (Immole in 5 mi di acetone e due gocce di trietilammina) sotto agitazione. Dopo 24 ore, la soluzione viene portata a secco sotto vuoto a pressione ridotta ed il solido grezzo, dissolto in cloroformio, è lavato con acqua. La fase organica, portata a secco, fornisce il composto grezzo dell’Esempio 2 che viene purificato per cromatografia su gel di silice (TLC o colonna eluente cloroformio-metanolo 70:30 w). Resa 65 %. MS (EI) m/z 326; 1H NMR (CDCI3) 7,10 (2H, d), 7,03 (2H, d), 5,78 (2H, d), 4.62 (2H, dd), 3,65 (4H, m), 3,18 (4H, m), 3, 07 (2H, d). Anal. Cale. CI8HI8N204, C, 66.25; H, 5.56; N, 8.58; Trovato C, 66.40; H, 5.52; N, 8.61. 2- (4-morpholin-4-ylphenyl) -3a, 4,7,7a-tetrahydro-1 / 7-4,7-epoxyisoindole-1,3-dione To a solution of maleimide (1 mmol) in benzene (10 ml) a solution of furan (1 mmol) in benzene (10 ml) is added dropwise at room temperature under stirring for three days. The mixture is brought to dryness, at 25 ° C and under reduced pressure, and the residue washed with ethyl ether. The white solid separated by filtration is dissolved in acetone and added drop by drop of a solution of 4- (4-chlorophenyl) morpholine (Immole in 5 ml of acetone and two drops of triethylamine) under stirring. After 24 hours, the solution is brought to dryness under vacuum at reduced pressure and the crude solid, dissolved in chloroform, is washed with water. The organic phase, brought to dryness, provides the crude compound of Example 2 which is purified by chromatography on silica gel (TLC or eluent column chloroform-methanol 70:30 w). Yield 65%. MS (EI) m / z 326; 1H NMR (CDCI3) 7.10 (2H, d), 7.03 (2H, d), 5.78 (2H, d), 4.62 (2H, dd), 3.65 (4H, m), 3, 18 (4H, m), 3.07 (2H, d). Anal. Cale. CI8HI8N204, C, 66.25; H, 5.56; N, 8.58; Found C, 66.40; H, 5.52; N, 8.61.
ESEMPIO 3 EXAMPLE 3
1 -butil- 1 H-pirrolo-2,5-dione 1-butyl- 1 H-pyrrole-2,5-dione
Il prodotto desiderato è stato preparato a partire da anidride maleica e butan-l-ammina. The desired product was prepared starting from maleic anhydride and butan-1-amine.
80%. MS (EI) m/z 153; 1H NMR (CDCI3) 6.98 (2H, s), 4.45 (2H, dd), 1.52 (2H, p), 1, 33 (2H, m), 1.02 (3H, t). Anal. Cale. C8HnN02C, 62.73; H, 7.24; N, 9.14; Trovato C, 62.75; H, 7.21; N, 9.16. 80%. MS (EI) m / z 153; 1H NMR (CDCI3) 6.98 (2H, s), 4.45 (2H, dd), 1.52 (2H, p), 1.33 (2H, m), 1.02 (3H, t). Anal. Cale. C8HnN02C, 62.73; H, 7.24; N, 9.14; Found C, 62.75; H, 7.21; N, 9.16.
ESEMPIO 4 EXAMPLE 4
1 -dodecil- 1 H-pirrolo-2,5 -dione 1 -dodecyl- 1H-pyrrole-2,5 -dione
Il prodotto desiderato è stato preparato a partire da anidride maleica e dodecan-1-ammina. Resa: 78%. MS (EI) m/z 265; 1H NMR (CDC13) 6.98 (2H, s), 4.39 (2H, t), 1.63 (2H, m), 1, 31 (16H, m), 0.91 (3H, t). Anal. Cale. Ci6H27N02C, 72.41; H, 10.25; N, 5.28; Trovato C, 72.50; H, 10.23; N, 5.26. The desired product was prepared starting from maleic anhydride and dodecan-1-amine. Yield: 78%. MS (EI) m / z 265; 1H NMR (CDC13) 6.98 (2H, s), 4.39 (2H, t), 1.63 (2H, m), 1, 31 (16H, m), 0.91 (3H, t). Anal. Cale. Ci6H27N02C, 72.41; H, 10.25; N, 5.28; Found C, 72.50; H, 10.23; N, 5.26.
ESEMPIO 5 EXAMPLE 5
(£)-l-(eptadec-8-enil)-lH-pirrolo-2,5-dione (£) -l- (heptadec-8-enyl) -lH-pyrrole-2,5-dione
Il prodotto desiderato è stato preparato a partire da anidride maleica e (£)-eptadec-8-en-1 -ammina. Resa: 69%. MS (EI) m/z 333; *H NMR (CDC13) 6.98 (2H, s), 5,45 (2H, s), 4.41 (2H, t), 2,20 (4H, dt), 1.63 (2H, m), 1, 31 (18H, m), 0.91 (3H, t). Anal. Cale. C2iH35N02C, 75 63; H 10 58; N 420; Trovato C 7567; H 1061; N, 4.18. The desired product was prepared starting from maleic anhydride and (£) -heptadec-8-en-1 -amine. Yield: 69%. MS (EI) m / z 333; * H NMR (CDC13) 6.98 (2H, s), 5.45 (2H, s), 4.41 (2H, t), 2.20 (4H, dt), 1.63 (2H, m), 1, 31 (18H , m), 0.91 (3H, t). Anal. Cale. C2iH35N02C, 75 63; H 10 58; N 420; Found C 7567; H 1061; N, 4.18.
Claims (10)
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