ITBO20070618A1 - USEFUL ORGANIC COMPOUNDS FOR THE TREATMENT OF NEURODEGENERATIVE DISEASES, THEIR UTILIZATIONS AND METHOD FOR THEIR PREPARATION - Google Patents
USEFUL ORGANIC COMPOUNDS FOR THE TREATMENT OF NEURODEGENERATIVE DISEASES, THEIR UTILIZATIONS AND METHOD FOR THEIR PREPARATION Download PDFInfo
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- ITBO20070618A1 ITBO20070618A1 IT000618A ITBO20070618A ITBO20070618A1 IT BO20070618 A1 ITBO20070618 A1 IT BO20070618A1 IT 000618 A IT000618 A IT 000618A IT BO20070618 A ITBO20070618 A IT BO20070618A IT BO20070618 A1 ITBO20070618 A1 IT BO20070618A1
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- 238000011282 treatment Methods 0.000 title claims description 25
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- -1 1Me Substances 0.000 claims description 33
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- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 1
- RVKRRKYBGKPJDF-UHFFFAOYSA-N tert-butyl 3-formyl-5-methoxyindole-1-carboxylate Chemical compound COC1=CC=C2N(C(=O)OC(C)(C)C)C=C(C=O)C2=C1 RVKRRKYBGKPJDF-UHFFFAOYSA-N 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
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- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 229940040064 ubiquinol Drugs 0.000 description 1
- QNTNKSLOFHEFPK-UPTCCGCDSA-N ubiquinol-10 Chemical compound COC1=C(O)C(C)=C(C\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CCC=C(C)C)C(O)=C1OC QNTNKSLOFHEFPK-UPTCCGCDSA-N 0.000 description 1
- 229940035936 ubiquinone Drugs 0.000 description 1
- 238000007738 vacuum evaporation Methods 0.000 description 1
- 235000012141 vanillin Nutrition 0.000 description 1
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- 229940041603 vitamin k 3 Drugs 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C225/00—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones
- C07C225/24—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones the carbon skeleton containing carbon atoms of quinone rings
- C07C225/26—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones the carbon skeleton containing carbon atoms of quinone rings having amino groups bound to carbon atoms of quinone rings or of condensed ring systems containing quinone rings
- C07C225/28—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones the carbon skeleton containing carbon atoms of quinone rings having amino groups bound to carbon atoms of quinone rings or of condensed ring systems containing quinone rings of non-condensed quinone rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/34—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups
- C07C233/35—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
- C07C233/40—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to an acyclic carbon atom of a carbon skeleton containing six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
- C07D311/70—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4 with two hydrocarbon radicals attached in position 2 and elements other than carbon and hydrogen in position 6
- C07D311/72—3,4-Dihydro derivatives having in position 2 at least one methyl radical and in position 6 one oxygen atom, e.g. tocopherols
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D339/00—Heterocyclic compounds containing rings having two sulfur atoms as the only ring hetero atoms
- C07D339/02—Five-membered rings
- C07D339/04—Five-membered rings having the hetero atoms in positions 1 and 2, e.g. lipoic acid
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated
Description
D E S C R I Z I O N E DESCRIPTION
La presente invenzione è relativa a composti organici, a composti organici per usi come medicamenti, ad usi di tali composti organici per la produzione di preparazioni farmaceutiche. La presente invenzione è, inoltre relativa a metodi per la sintesi dei menzionati composti organici. The present invention relates to organic compounds, to organic compounds for uses as medicaments, to uses of such organic compounds for the production of pharmaceutical preparations. The present invention also relates to methods for the synthesis of the aforementioned organic compounds.
Le malattie neurodegenerative sono un gruppo di disordini caratterizzati da una progressiva perdita delle strutture anatomiche e fisiologiche dei neuroni. Sebbene la loro eziologia non sia stata definitivamente chiarita, si è dimostrato che tra le cause principali si possono annoverare lo stress ossidativo e i processi di precipitazione di proteine con la formazione di aggregati fibrillari. Neurodegenerative diseases are a group of disorders characterized by a progressive loss of the anatomical and physiological structures of neurons. Although their etiology has not been definitively clarified, it has been shown that oxidative stress and the processes of protein precipitation with the formation of fibrillar aggregates can be included among the main causes.
infatti, una maggiore sensibilità ad uno stato di eccesso ossidativo (causa e conseguenza di disfunzioni mitocondriali) si riscontra soprattutto nei tessuti e negli organi contraddistinti da un elevato consumo di ossigeno, come il cervello, cosi come la formazione di aggregati proteinacei caratterizza sia la malattia di Alzheimer (AD) che il morbo di Parkinson (PD) ed il morbo di Huntington (HD). in fact, a greater sensitivity to an oxidative excess state (cause and consequence of mitochondrial dysfunctions) is found above all in tissues and organs characterized by a high oxygen consumption, such as the brain, as well as the formation of proteinaceous aggregates characterizes both the disease Alzheimer's disease (AD), Parkinson's disease (PD) and Huntington's disease (HD).
A questo riguardo, si noti che studi recenti hanno evidenziato che il danno ossidativo riveste un ruolo importante nel calo delle capacità cognitive che accompagna l'invecchiamento [Lu, T. et al. Gene Regulation and DNA damage in thè ageing Human Brain. Nature 429:883-891(2004)]. In this regard, it should be noted that recent studies have shown that oxidative damage plays an important role in the decline in cognitive abilities that accompanies aging [Lu, T. et al. Gene Regulation and DNA damage in the aging Human Brain. Nature 429: 883-891 (2004)].
In base a queste evidenze sperimentali, dai risultati insoddisfacenti dei trattamenti clinici finora utilizzati, si è giunti alla conclusione che l'impiego di un singolo antiossidante potrebbe non essere sufficiente ad un'adeguata terapia per queste patologie. Poiché molti altri processi contribuiscono alla patogenesi, un trattamento singolo risulta poco benefico. On the basis of these experimental evidences, from the unsatisfactory results of the clinical treatments used so far, it was concluded that the use of a single antioxidant may not be sufficient for an adequate therapy for these pathologies. Since many other processes contribute to pathogenesis, a single treatment is of little benefit.
Inoltre, è importante sottolineare che vi sono altre patologie, oltre alla AD, al PD ed al HD, caratterizzate da depositi di Αβ. Tra queste patologie ricordiamo: la sindrome di Down, l'emorragia celebrale ereditaria associata alla amiloidosi del "tipo-olandese", amiloidosi associata ad infiammazioni croniche, amiloidosi associata a mielomi multipli e altre discrasie delle cellule ematiche B linfoidi, amiloidosi associata al diabete di tipo II, amiloidosi associata a malattie derivanti da prioni come la malattia di Creutzfeldt-Jackob, la sindrome di Gertsmann-Straussler, malattia di Kuru e scrapie delle pecore (WO 02/00603). Furthermore, it is important to underline that there are other pathologies, in addition to AD, PD and HD, characterized by Αβ deposits. Among these pathologies we remember: Down syndrome, hereditary cerebral haemorrhage associated with "Dutch-type" amyloidosis, amyloidosis associated with chronic inflammation, amyloidosis associated with multiple myelomas and other dyscrasias of blood B lymphoid cells, amyloidosis associated with diabetes type II, amyloidosis associated with prion-related diseases such as Creutzfeldt-Jackob disease, Gertsmann-Straussler syndrome, Kuru disease and sheep scrapie (WO 02/00603).
Nel campo dei prodotti farmaceutici per la cura della AD la domanda di brevetto PCT/IT03/00227 ha portato all'identificazione di una nuova famiglia di derivati 2,5-bis-diammino-[1,4]benzochinonìci, che hanno dimostrato, tra le altre proprietà, attività relativamente elevate per il trattamento della AD in mammiferi. In the field of pharmaceutical products for the treatment of AD, the patent application PCT / IT03 / 00227 has led to the identification of a new family of 2,5-bis-diamino- [1,4] benzoquinone derivatives, which have shown, among the other properties, relatively high activities for the treatment of AD in mammals.
Non esistono, tuttavia, a tutt'oggi trattamenti terapeutici in grado di arrestare la progressione della malattia, sebbene siano stati recentemente introdotti sul mercato alcuni farmaci mirati soprattutto al controllo dei sintomi cognitivi. Questi farmaci - tacrina (Cognex<®>), donepezil (Aricept<®>) rivastigmina {Exelon<®>) e galantamina (Reminyl<®>)- sono accomunati dallo stesso meccanismo d'azione, che consiste nell'inibizione dell'acetilcolina esterasi (AChE). However, to date there are no therapeutic treatments capable of arresting the progression of the disease, although some drugs aimed mainly at controlling cognitive symptoms have recently been introduced on the market. These drugs - tacrine (Cognex <®>), donepezil (Aricept <®>), rivastigmine {Exelon <®>) and galantamine (Reminyl <®>) - share the same mechanism of action, which consists in the inhibition of acetylcholine esterase (AChE).
Da quanto sopraesposto si desume anche che vi è ancora una notevole necessità di rendere disponibili nuovi medicamenti per il trattamento di patologie neurodegenerative, di patologie caratterizzate da depositi di Αβ e di patologie caratterizate da disfunzioni mitocondriali; in particolare AD. From the foregoing it can also be deduced that there is still a considerable need to make new medicaments available for the treatment of neurodegenerative pathologies, pathologies characterized by Αβ deposits and pathologies characterized by mitochondrial dysfunctions; in particular AD.
Scopo della presente invenzione è quello di fornire composti utilizzabili vantaggiosamente per il trattamento di patologie neurodegenerative, di patologie caratterizzate da depositi di Αβ e di patologie caratterizate da disfunzioni mitocondriali; in particolare AD. The object of the present invention is to provide compounds which can be advantageously used for the treatment of neurodegenerative pathologies, of pathologies characterized by αβ deposits and of pathologies characterized by mitochondrial dysfunctions; in particular AD.
Secondo la presente invenzione vengono fom iti composti organici, composti organici per usi come medicamenti, usi di composti organici per la produzione di preparazioni farmaceutiche e metodi di sintesi di tali composti secondo quanto licitato nelle rivendicazioni indipendenti che seguono e, preferibilmente, in una qualsiasi delle rivendicazioni dipendenti direttamente o indirettamente dalle rivendicazioni indipendenti. According to the present invention, organic compounds are formed, organic compounds for uses as medicaments, uses of organic compounds for the production of pharmaceutical preparations and methods of synthesis of such compounds according to what is disclosed in the independent claims which follow and, preferably, in any of the claims directly or indirectly dependent on independent claims.
A meno che non sia specificato esplicitamente il contrario, i seguenti termini presentano il significato indicato qui sotto. Unless otherwise explicitly specified, the following terms have the meanings given below.
Nel presente testo per "sale farmaceuticamente accettabile" si intende un sale che mantiene le proprietà biologiche del composto di partenza. Esempi non limitativi di metodologie per la preparazione di tali sali includono le seguenti: addizione di acidi inorganici {ad esempio acido cloridrico, acido bromidrico, acido solforico, acido fosforico e simili) od organici (ad esempio acido acetico, acido ossalico, acido maleico, acido metansolfonico, acido salicilico, acido succinico, acido citrico e simili) ad una base libera del composto di partenza,-sostituzione di un protone acido del composto di partenza con catione metallico (ad esempio un catione di un metallo alcalino o di un alluminio o simili); trasferimento di un protone acido del composto di partenza ad una base organica (ad esempio dimetilammina, trietilammina e simili) e coordinamento con tale base organica. I composti oggetto della presente invenzione sono da intendersi, a meno che non venga specificato il contrario, come comprendenti loro sali farmaceuticamente accettabili. In the present text, by "pharmaceutically acceptable salt" is meant a salt which maintains the biological properties of the starting compound. Non-limiting examples of methodologies for the preparation of such salts include the following: addition of inorganic acids (e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid and the like) or organic acids (e.g. acetic acid, oxalic acid, maleic acid, methanesulfonic acid, salicylic acid, succinic acid, citric acid and the like) to a free base of the starting compound, - substitution of an acid proton of the starting compound with a metal cation (for example a cation of an alkali metal or an aluminum or similar); transfer of an acid proton of the starting compound to an organic base (for example dimethylamine, triethylamine and the like) and coordination with this organic base. The compounds object of the present invention are to be understood, unless otherwise specified, as comprising their pharmaceutically acceptable salts.
In questo testo per "prò-medicina" ("prodrug") si intende un agente che in vivo viene convertito in una sostanza farmacologicamente attiva. Una pro-medicina può presentare alcuni vantaggi rispetto alla corrispondente sostanza farmacologicamente attiva. Ad esempio, può essere più facile da somministrare ai pazienti e/o avere una maggiore solubilità e/o una migliore capacità di attraversare le membrane cellulari. I composti oggetto della presente invenzione sono da intendersi come comprendenti eventuali loro pro-medicine. I composti oggetto della presente invenzione possono agire come pro-medicine di ulteriori sostanze farmacologicamente attive. In this text, "pro-medicine" ("prodrug") means an agent which is converted in vivo into a pharmacologically active substance. A pro-medicine may have some advantages over the corresponding pharmacologically active substance. For example, it may be easier to administer to patients and / or have higher solubility and / or better ability to cross cell membranes. The compounds object of the present invention are to be understood as including their possible pro-medicines. The compounds object of the present invention can act as pro-medicines of further pharmacologically active substances.
Alcuni composti del presente testo possono presentare uno o più centri asimmetrici; tali composti possono, pertanto, essere prodotti come stereoisomeri (R)- o (S)- o come loro miscele. I composti identificati nel presente testo sono da intendersi, a meno che non venga specificato altrimenti, come includenti sia gli isomeri presi individualmente sia loro miscele, racemiche o di altro genere. Metodi per la determinazione della stereochimica e la separazione degli stereoisomeri sono noti nello stato dell'arte (si veda, ad esempio, il Capitolo 4 di "Advanced Organic Chemistry", 4<a>edizione L. March, John Wiley and Sons, New York, 1992). Some compounds of this text may have one or more asymmetric centers; such compounds can, therefore, be produced as stereoisomers (R) - or (S) - or as mixtures thereof. The compounds identified in this text are to be understood, unless otherwise specified, as including both the isomers individually and their mixtures, racemic or otherwise. Methods for the determination of stereochemistry and separation of stereoisomers are known in the state of the art (see, for example, Chapter 4 of "Advanced Organic Chemistry", 4 <a> edition L. March, John Wiley and Sons, New York, 1992).
I composti identificati nel presente testo possono presentare fenomeni di tautomeria; tali composti sono da intendersi, a meno che non venga specificato altrimenti, come comprendenti forme tautomeriche prese sia individualmente sia in miscele . The compounds identified in this text may exhibit tautomerism phenomena; such compounds are to be understood, unless otherwise specified, as comprising tautomeric forms taken either individually or in mixtures.
Nel presente testo "Cx-Cy" viene riferito ad un gruppo che si intende come presentante da x ad y atomi di carbonio. In the present text "Cx-Cy" refers to a group which is intended as having x to y carbon atoms.
Nel presente testo per "alifatico" si intende un idrocarburo non aromatico e non sostituito, saturo od insaturo, lineare, ramificato e/o ciclico. Esempi non limitativi di gruppi alifatici sono: t-butil, etenil, 1- o 2-propenil, cicloesil. In the present text, "aliphatic" means a non-aromatic and unsubstituted, saturated or unsaturated, linear, branched and / or cyclic hydrocarbon. Non-limiting examples of aliphatic groups are: t-butyl, ethenyl, 1- or 2-propenyl, cyclohexyl.
Nel presente testo per "alchile" si intende un alifatico saturo (vale a dire un gruppo alifatico privo di doppi o tripli legami carbonio-carbonio). Esempi non limitativi di alchili sono: metil, npropil, t-butil, cicloesil. In the present text, "alkyl" means a saturated aliphatic (ie an aliphatic group devoid of double or triple carbon-carbon bonds). Non-limiting examples of alkyls are: methyl, npropyl, t-butyl, cyclohexyl.
Nel presente testo per "alcossi" si intende un alifatico (preferibilmente un alifatico C1-C5, vantaggiosamente un alchile C1-C4) legato alla rimanente parte della molecola attraverso un atomo di ossigeno. Esempi non limitativi di gruppi alcossi sono: metossi, etossi. In the present text, "alkoxy" means an aliphatic (preferably a C1-C5 aliphatic, advantageously a C1-C4 alkyl) bonded to the remaining part of the molecule through an oxygen atom. Non-limiting examples of alkoxy groups are: methoxy, ethoxy.
Nel presente testo per "Bn" si intende un benzile . In this text, "Bn" means a benzyl.
In accordo con un primo aspetto della presente invenzione viene fornito un conposto presentante formula generale (I): In accordance with a first aspect of the present invention, a compound is provided having general formula (I):
o suoi isomeri geometrici, sue forme otticamente attive, diastereoisomeri, sue forme raceme, o suoi sali farmaceuticamente accettabili, o sue promedicine, o its geometric isomers, its optically active forms, diastereomers, its racemic forms, or its pharmaceutically acceptable salts, or its promedicines,
in cui R<2>, R<3>, R<6>, R<7>sono scelti, ciascuno indipendentemente dall'altro, in un gruppo consistente di: idrogeno e alchile C1-C5; wherein R <2>, R <3>, R <6>, R <7> are selected, each independently of the other, from a group consisting of: hydrogen and C1-C5 alkyl;
R<4>e R<5>rappresentano, ciascuno indipendentemente dall'altro, un sostituente scelto nel gruppo consistente in: idrogeno, alchile C1-C4, OMe, SMe, C1, F, Br e Ph (preferibilmente, idrogeno, alchile C1-C4, OMe e SMe); R <4> and R <5> represent, each independently of the other, a substituent selected from the group consisting of: hydrogen, C1-C4 alkyl, OMe, SMe, C1, F, Br and Ph (preferably, hydrogen, C1 alkyl -C4, OMe and SMe);
Z<1>e Z<2>rappresentano, ciascuno indipendentemente dall'altro, un rispettivo alifatico C2-C9, in particolare un alchile; Z <1> and Z <2> represent, each independently of the other, a respective C2-C9 aliphatic, in particular an alkyl;
almeno uno tra R<1>ed R<8>rappresenta, indipendentemente dall'altro, un gruppo antiossidante e/o, secondo alcune forme di attuazione, antiamiloideo . at least one of R <1> and R <8> represents, independently of the other, an antioxidant group and / or, according to some embodiments, antiamyloid.
Vantaggiosamente, almeno uno tra R<1>ed R<8>(secondo alcune forme di attuazione entrambi) rappresenta, indipendentemente dall'altro, un gruppo antiossidante in grado di ridurre il chinone in idrochinone . Advantageously, at least one of R <1> and R <8> (according to some embodiments both) represents, independently of the other, an antioxidant group capable of reducing quinone to hydroquinone.
Secondo alcune forme di attuazione, R<1>ed R<8>sono scelti, ciascuno indipendentemente dall'altro, in un gruppo consistente di: According to some embodiments, R <1> and R <8> are chosen, each independently from the other, in a group consisting of:
in cui R<9>, R<10>, R<18>, R<20>, R<13>, rappresentano, ciascuno indipendentemente dagli altri un rispettivo alchile, in particolare C1-C5; wherein R <9>, R <10>, R <18>, R <20>, R <13>, each independently from the others represent a respective alkyl, in particular C1-C5;
R<11>, R<12>, R<14>, R<15>, R<16>, R<17>, R<19>rappresentano, ciascuno indipendentemente dagli altri un rispettivo alchile, in particolare C1-C3; R <11>, R <12>, R <14>, R <15>, R <16>, R <17>, R <19> represent, each independently of the others, a respective alkyl, in particular C1-C3;
con la condizione che se uno tra R<1>ed R<8>è with the proviso that if one of R <1> and R <8> is
l'altro tra R<1>ed R<8>è scelto nel gruppo consistente di: the other between R <1> and R <8> is chosen from the group consisting of:
vantaggiosamente, nel composto avente formula generale (I), quando uno tra R<1>ed R<8>è advantageously, in the compound having general formula (I), when one of R <1> and R <8> is
l'altro tra R<1>ed R<8>è: the other between R <1> and R <8> is:
Secondo alcune forme di attuazione, R<4>e R<5>rappresentano, ciascuno indipendentemente dall'altro, un sostituente scelto nel gruppo consistente in: idrogeno, alchile C1-C3. According to some embodiments, R <4> and R <5> represent, each independently of the other, a substituent selected from the group consisting of: hydrogen, C1-C3 alkyl.
Vantaggiosamente, R<4>e R<5>rappresentano, ciascuno, un rispettivo idrogeno. Vantaggiosamente, Z<1>e Z<2>rappresentano, ciascuno indipendentemente dall'altro, un alifatico (in particolare un alchile), vantaggiosamente C3-C6. Advantageously, R <4> and R <5> each represent a respective hydrogen. Advantageously, Z <1> and Z <2> represent, each independently of the other, an aliphatic (in particular an alkyl), advantageously C3-C6.
Secondo alcune forme di attuazione, R<2>, R<3>, R<6>, R<7>sono scelti, ciascuno indipendentemente dall'altro, in un gruppo consistente di: idrogeno e alchile, vantaggiosamente C1-C2. According to some embodiments, R <2>, R <3>, R <6>, R <7> are selected, each independently of the other, from a group consisting of: hydrogen and alkyl, advantageously C1-C2.
Secondo alcune forme di attuazione, R<8>rappresenta : According to some embodiments, R <8> represents:
Vantaggiosamente, R<9>rappresenta un alchile C3-C5. Secondo particolari forme di attuazione, R<1>rappresenta: Advantageously, R <9> represents a C3-C5 alkyl. According to particular embodiments, R <1> represents:
vantaggiosamente, R<9>rappresenta C4H8, in particolare lineare (n-butil). Vantaggiosamente, R<20>rappresenta un alchile C1-C4. advantageously, R <9> represents C4H8, in particular linear (n-butyl). Advantageously, R <20> represents a C1-C4 alkyl.
Secondo specifiche forme di attuazione, il composto avente formula generale (I) presenta una delle seguenti strutture: According to specific embodiments, the compound having general formula (I) has one of the following structures:
Secondo alcune forme di attuazione, R<8>rappresenta: According to some embodiments, R <8> represents:
Vantaggiosamente, R , R , R , R rappresentano, ciascuno indipendentemente dagli altri un alchile C1-C3; R<13>rappresenta un alchile C1-C4. Advantageously, R, R, R, R represent, each independently from the others, a C1-C3 alkyl; R <13> represents a C1-C4 alkyl.
Vantaggiosamente, R<14>, R<15>, R<16>, R<17>rappresentano, ciascuno, un rispettivo metile; R<13>, rappresenta un CH2. Vantaggiosamente, R<1>ed R<8>sono tra loro uguali. Advantageously, R <14>, R <15>, R <16>, R <17> each represent a respective methyl; R <13>, represents a CH2. Advantageously, R <1> and R <8> are equal to each other.
Secondo una specifica forma di attuazione, il composto avente formula generale (I) presenta la seguente struttura: According to a specific embodiment, the compound having general formula (I) has the following structure:
Secondo alcune forme di attuazione R rappresenta : According to some embodiments R represents:
Vantaggiosamente, R<10>rappresenta un alchile C1-C4; R<11>rappresenta un alchile C1-C3. Advantageously, R <10> represents a C1-C4 alkyl; R <11> represents a C1-C3 alkyl.
Vantaggiosamente, R<11>rappresenta un metile; R<10>, rappresenta un CH2. Vantaggiosamente, R<1>ed R<8>sono tra loro uguali. Advantageously, R <11> represents a methyl; R <10>, represents a CH2. Advantageously, R <1> and R <8> are equal to each other.
Vantaggiosamente, z<1>e z<2>rappresentano, ciascuno indipendentemente dall'altro un C6HI2, in particolare lineare (n-esil). Advantageously, z <1> and z <2> represent, each independently of the other, a C6HI2, in particular linear (n-hexyl).
Secondo una specifica forma di attuazione il composto avente formula generale (I) presenta la seguente struttura: According to a specific embodiment, the compound having general formula (I) has the following structure:
Secondo ulteriori forme di attuazione, rappresenta: According to further embodiments, it represents:
Vantaggiosamente, R<18>rappresenta un alchile C1-C4; R<12>rappresenta un alchile C1-C3. Advantageously, R <18> represents a C1-C4 alkyl; R <12> represents a C1-C3 alkyl.
Vantaggiosamente, R<12>rappresenta un metile,· R<18>, rappresenta un CH2; R<1>ed R<8>sono tra loro uguali. Advantageously, R <12> represents a methyl, · R <18>, represents a CH2; R <1> and R <8> are equal to each other.
Secondo una specifica forma di attuazione, il composto avente formula generale (I) presenta la seguente struttura: According to a specific embodiment, the compound having general formula (I) has the following structure:
Secondo alcune forme di attuazione, almeno uno tra R<1>ed R<8>rappresenta, indipendentemente dall ' altro un rispettivo gruppo in grado di contrastare l'aggregazione amiloidea. According to some embodiments, at least one of R <1> and R <8> represents, independently of the other, a respective group capable of counteracting amyloid aggregation.
Secondo alcune forme di attuazione, almeno uno tra R<1>ed R<8>presenta la formula generale (XVII): According to some embodiments, at least one of R <1> and R <8> has the general formula (XVII):
in cui Alo è un alogeno, R<22>è un ali fatico C1-C4e R<21>è scelto tra: C=0 e in which Alo is a halogen, R <22> is an aliphatic C1-C4 and R <21> is chosen between: C = 0 and
in cui R<23>è un alifatico C2-C7ed il carbonile è legato direttamente al carbonio benzilico. wherein R <23> is a C2-C7 aliphatic and the carbonyl is directly bonded to the benzyl carbon.
vantaggiosamente. Alo è fluoro, vantaggiosamente, R<22>rappresenta un alchile C1-C2ed R<23>è un alchile C2-C4. advantageously. Halo is fluorine, advantageously, R <22> represents a C1-C2 alkyl and R <23> is a C2-C4 alkyl.
vantaggiosamente, R<1>ed R<8>sono tra loro uguali. Secondo alcune forme di attuazione, R<21>è C=O. Secondo una specifica forma di attuazione, il composto avente formula generale (I) presenta la seguente struttura: advantageously, R <1> and R <8> are equal to each other. According to some embodiments, R <21> is C = O. According to a specific embodiment, the compound having general formula (I) has the following structure:
Secondo alcune forme di attuazione, R è According to some embodiments, R is
; R<1>ed R<8>sono tra loro uguali. ; R <1> and R <8> are equal to each other.
Secondo una specifica forma di attuazione, il composto avente formula generale (I) presenta la seguente struttura: According to a specific embodiment, the compound having general formula (I) has the following structure:
I composti che ricadono all'interno della formila generale (I) come sopra definita sono composti multifunzionali in grado di inibire lo stress ossidativo a livello mitocondriale e contemporaneamente il processo amiloidogenico caratteristico delle neurodegenerazioni quali AD, PD, HD e malattie prioniche. The compounds that fall within the general formula (I) as defined above are multifunctional compounds capable of inhibiting oxidative stress at the mitochondrial level and simultaneously the amyloidogenic process characteristic of neurodegenerations such as AD, PD, HD and prion diseases.
Rispetto alle molecole (Memoquin) descritte nella domanda di brevetto PCT/IT03/00227 i composti che ricadono all'interno della formula generale (I) come sopra definita hanno una attività antiossidante e/o antiamiloidea potenziata. In particolare, i composti che ricadono all'interno della formula generale (I), in cui almeno uno tra R<1>ed R<8>presenta la formula generale (XVII), hanno una attività amiloidea antiaggregante potenziata; i composti che ricadono all'interno della formula generale (I), in cui almeno uno tra R<1>ed R<8>presenta la formula generale (II), (III), (IV), (V) oppure (VI), hanno una attività antiossidante potenziata. Compared to the molecules (Memoquin) described in the patent application PCT / IT03 / 00227, the compounds that fall within the general formula (I) as defined above have an enhanced antioxidant and / or antiamyloid activity. In particular, the compounds that fall within the general formula (I), in which at least one of R <1> and R <8> has the general formula (XVII), have an enhanced antiplatelet amyloid activity; compounds falling within the general formula (I), in which at least one of R <1> and R <8> has the general formula (II), (III), (IV), (V) or (VI ), have enhanced antioxidant activity.
In particolare, i composti che ricadono all'interno della formula generale (I) come sopra definita combinano in un'unica molecola due antiossidanti motocondriali: il coenzima Q10 da una parte e dall'altra parte l'acido α-lipoico e/o la curcumina e/o la melatonina e/o vitamina E. Alternativamente combinano in un'unica molecola una funzione antiossidante (coenzima Q10) e una antiamiloidea quale il composto flurbiprofene. In particular, the compounds that fall within the general formula (I) as defined above combine two motocondrial antioxidants in a single molecule: coenzyme Q10 on one side and α-lipoic acid on the other and / or curcumin and / or melatonin and / or vitamin E. Alternatively they combine in a single molecule an antioxidant function (coenzyme Q10) and an antiamyloid such as the flurbiprofen compound.
Si è in pratica sfruttato il residuo 2,5-diammino-1,4-benzochinonico come scaffold ad attività antiossidante, su cui sono stati inseriti opportuni residui molecolari in grado di inibire la precipitazione delle proteine amiloidogeniche e/o di potenziare l'attività antiossidante. In practice, the 2,5-diamino-1,4-benzoquinone residue has been exploited as a scaffold with antioxidant activity, on which appropriate molecular residues able to inhibit the precipitation of amyloidogenic proteins and / or to enhance the antioxidant activity have been inserted. .
In particolare, visto che l'acido lipoico è in grado di ridurre l'ubichinone ad ubichinolo, attraverso il trasferimento di una coppia di elettroni, questi ibridi risultano possedere una potente attività antiossidante, in quanto il frammento dell'acido lipoico dovrebbe mantenere il chinone nella forma idrochinonica, dotata di attività radicai scavenger. Inoltre, i due scaffold con cui sono state create le molecole, sono substrati naturali di enzimi mitocondriali che mantengono l'acido lipoico e Q10 nello stato ridotto. In particular, since lipoic acid is able to reduce ubiquinone to ubiquinol, through the transfer of a pair of electrons, these hybrids have a powerful antioxidant activity, as the lipoic acid fragment should maintain the quinone in the hydroquinone form, with root-scavenger activity. Furthermore, the two scaffolds with which the molecules were created are natural substrates of mitochondrial enzymes that keep lipoic acid and Q10 in the reduced state.
Tutte queste considerazioni molecolari e biochimiche fanno dei composti sopra-riportati), in cui almeno uno tra R<1>ed R<8>presenta la formula generale (II), (III), (IV), (V) oppure (VI), dei buoni antiossidanti, in quanto secondo le nostre conoscenze e la ricerca bibliografica effettuata, sono gli unici ad inglobare nella stessa entità chimica due funzioni antiossidanti in grado di contrastare il processo ossidativo alla base della neurodegenerazione in due punti distinti. All these molecular and biochemical considerations make the above-mentioned compounds), in which at least one of R <1> and R <8> has the general formula (II), (III), (IV), (V) or (VI ), good antioxidants, as according to our knowledge and bibliographic research carried out, they are the only ones to incorporate in the same chemical entity two antioxidant functions capable of counteracting the oxidative process at the base of neurodegeneration in two distinct points.
I nuovi derivati presentano anche un elevato potenziale antiaggregante. The new derivatives also have a high antiplatelet potential.
In considerazione di quanto sopra esposto, in accordo con ulteriori aspetti della presente invenzione, viene fornito un composto presentante formula generale (I), come sopra definita, per un uso come medicamento. In particolare, per il trattamento di patologie caratterizzate da depositi di β-amiloide (Αβ) in mammiferi e/o di patologie caratterizzate da disfunzione mitocondriale e/o di patologie neurodegenerative; in particolare, la malattia di Alzheimer e/o il morbo di Parkinson e/o il morbo di Huntington. In consideration of the above, in accordance with further aspects of the present invention, a compound is provided having general formula (I), as defined above, for use as a medicament. In particular, for the treatment of pathologies characterized by β-amyloid (Αβ) deposits in mammals and / or of pathologies characterized by mitochondrial dysfunction and / or neurodegenerative pathologies; in particular, Alzheimer's disease and / or Parkinson's disease and / or Huntington's disease.
In accordo con ulteriori aspetti della presente invenzione, vengono fom iti usi di un composto presentante formula generale (I) come sopra definita, per la produzione di una preparazione farmaceutica per il trattamento di patologie caratterizzate da depositi di β-amiloide (Αβ) in mammiferi e/o di patologie caratterizzate da disfunzione mitocondriale e/o di patologie neurodegenerative,· in particolare, la malattia di Alzheimer e/o il morbo di Parkinson e/o il morbo di Huntington. In accordance with further aspects of the present invention, uses of a compound having general formula (I) as defined above are provided for the production of a pharmaceutical preparation for the treatment of pathologies characterized by β-amyloid (Αβ) deposits in mammals. and / or diseases characterized by mitochondrial dysfunction and / or neurodegenerative diseases, in particular, Alzheimer's disease and / or Parkinson's disease and / or Huntington's disease.
In accordo con ulteriori aspetti della presente invenzione viene forn ito un metodo per il trattamento della di patologie caratterizzate da depositi di βamiloide (Αβ) in mammiferi e/o di patologie caratterizzate da disfunzione mitocondriale e/o di patologie neurodegenerative; in particolare, la malattia di Alzheimer e/o il morbo di Parkinson e/o il morbo di Huntington. Il metodo prevede di somministrare al detto mammifero una quantità efficace di un composto presentante formula generale (I), come sopra definita In accordance with further aspects of the present invention, a method is provided for the treatment of pathologies characterized by βamyloid (Αβ) deposits in mammals and / or of pathologies characterized by mitochondrial dysfunction and / or neurodegenerative pathologies; in particular, Alzheimer's disease and / or Parkinson's disease and / or Huntington's disease. The method provides for administering to said mammal an effective amount of a compound having general formula (I), as defined above
In accordo con un'ulteriore aspetto della presente invenzione, viene fornita una preparazione farmaceutica comprendente un coirposto presentante formula generale (I), come sopra definita, o un suo sale farmaceuticamente accettabile ed un eccipiente e/o diluente farmaceuticamente accettabile. In accordance with a further aspect of the present invention, a pharmaceutical preparation is provided comprising a compound having general formula (I), as defined above, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient and / or diluent.
I composti ricadenti all'interno della formula generale (I) possono essere formulati, in modo noto, per somministrazioni parenterali per iniezione o somministrazione continua. Formulazioni per iniezione possono essere in forma di dosi unitarie, per esempio in ampolle o contenitori multidose contenenti conservanti. La composizione può essere in forma di sospensione, in liquidi acquosi o oleosi, e può contenere elementi della formulazione come agenti di dispersione e di stabilizzazione. In alternativa, il composto attivo può essere in polvere per essere disciolto appena prima dell'uso in un liquido all'uopo, per esempio acqua sterilizzata. The compounds falling within the general formula (I) can be formulated, in a known way, for parenteral administration by injection or continuous administration. Injection formulations can be in unit dose form, for example in ampoules or multidose containers containing preservatives. The composition may be in suspension form, in aqueous or oily liquids, and may contain formulation elements such as dispersing and stabilizing agents. Alternatively, the active compound can be in powder form to be dissolved just before use in a liquid for this purpose, for example sterilized water.
I composti ricadenti all'interno della formula generale (I) possono essere formulati per somministrazioni rettali come supposte o enteroclismi, per esempio contenenti eccipienti per supposte di tipo noto come per esempio burro di cacao od altri gliceridi. The compounds falling within the general formula (I) can be formulated for rectal administration as suppositories or enemas, for example containing excipients for known type suppositories such as for example cocoa butter or other glycerides.
I composti ricadenti all'interno della formula generale (I) possono anche essere formulati, in modo noto, come composizioni a rilascio prolungato. Queste composizioni a rilascio prolungato possono essere somministrate mediante un impianto (per esempio subcutaneo, o intramuscolare) o mediante un'iniezione intramuscolare. Pertanto, per esempio, i composti compresi all'interno della formula generale (I) possono essere formulati con adatti materiali polimerici o idrofobici (per esempio una emulsione o un olio) o resine a scambio ionico, o derivati relativamente poco solubili, come sali relativamente poco solubili. The compounds falling within the general formula (I) can also be formulated, in a known way, as extended release compositions. These sustained release compositions can be administered by an implant (e.g., subcutaneous, or intramuscular) or by an intramuscular injection. Therefore, for example, the compounds included within the general formula (I) can be formulated with suitable polymeric or hydrophobic materials (e.g. an emulsion or an oil) or ion exchange resins, or relatively poorly soluble derivatives, such as relatively salts. slightly soluble.
Per somministrazioni intranasali, i composti conpresi all'interno della formula generale (I) possono essere formulati per somministrazioni attraverso un dispositivo (noto), per esempio in polvere con un trasportatore adatto. For intranasal administrations, the compounds included within the general formula (I) can be formulated for administration through a (known) device, for example in powder form with a suitable carrier.
I dosaggi dei composti ricadenti all'interno della formula generale (I) dipenderanno dall'età e dalle condizioni del paziente, pertanto il preciso dosaggio dovrebbe essere deciso volta per volta dal medico. Il dosaggio dipenderà anche dal modo di somministrazione e dal particolare composto selezionato. Dosi utilizzabili possono essere per esempio comprese fra 0,1 mg/Kg e 400 mg/Kg rispetto al peso del corpo al giorno. The dosages of the compounds falling within the general formula (I) will depend on the age and condition of the patient, therefore the precise dosage should be decided by the physician on a case-by-case basis. The dosage will also depend on the method of administration and the particular compound selected. Usable doses can for example be comprised between 0.1 mg / kg and 400 mg / kg with respect to the body weight per day.
I composti ricadenti all'interno della formula generale (I), possono essere somministrati in combinazione con uno o più agenti terapeutici adatti e formulati in ogni maniera nota utilizzabile. The compounds falling within the general formula (I), can be administered in combination with one or more suitable therapeutic agents and formulated in any known usable way.
Secondo un'ulteriore aspetto della presente invenzione viene fornito un metodo per la sintesi di un composto presentante formula generale (I), come sopra definita, comprendente una fase di sostituzione nucleofila, in cui su un p-benzochinone avente formula generale (VII): According to a further aspect of the present invention, a method is provided for the synthesis of a compound having general formula (I), as defined above, comprising a nucleophilic substitution step, in which on a p-benzoquinone having general formula (VII):
in cui LG rappresenta un gruppo uscente presentante un effetto induttivo elettron attrattore, viene effettuata una sostituzione con un primo composto intennedio avente formula generale (Vili): in which LG represents a leaving group having an electron-withdrawing inductive effect, a substitution is made with a first intermediate compound having general formula (VIII):
in modo da ottenere composto presentante formula generale (I); R<1>, R<2>, R<3>, R<4>, R<5>, R<6>, R<7>, R<8>, Z<1>, Z<2>, sono definiti come sopra. so as to obtain compound having general formula (I); R <1>, R <2>, R <3>, R <4>, R <5>, R <6>, R <7>, R <8>, Z <1>, Z <2>, are defined as above.
Vantaggiosamente, durante la sostituzione nucleofila su un p-benzochinone avente formula generale (IX): Advantageously, during the nucleophilic substitution on a p-benzoquinone having general formula (IX):
, in cui vengono effettuate sostituzioni con composti intermedi aventi formule generali (Vili) e (X)= , in which substitutions are made with intermediate compounds having general formulas (VIII) and (X) =
Vantaggiosamente, i composti intermedi aventi formule generali (VIII) e (X) sono tra loro uguali. Advantageously, the intermediate compounds having general formulas (VIII) and (X) are equal to each other.
Secondo alcune preferite forme di attuazione LG rappresenta un gruppo alcossi C1-C4, vantaggiosamente un gruppo metossi. According to some preferred embodiments LG represents a C1-C4 alkoxy group, advantageously a methoxy group.
Secondo alcune forme di attuazione, la fase di sostituzione nucleofila avviene in presenza di un solvente alcolico, in particolare etanolo. La fase di sostituzione nucleofila avviene ad una temperatura tra 50° C e 65°C. According to some embodiments, the nucleophilic substitution step takes place in the presence of an alcoholic solvent, in particular ethanol. The nucleophilic substitution phase occurs at a temperature between 50 ° C and 65 ° C.
Secondo alcune forme di attuazione, il metodo comprende una fase di idrolisi, in cui un ulteriore composto intermedio avente formula generale (XI): According to some embodiments, the method comprises a hydrolysis step, in which a further intermediate compound having general formula (XI):
viene idrolizzato in modo da ottenere il detto primo composto intermedio di formula generale (VIII). it is hydrolyzed so as to obtain said first intermediate compound of general formula (VIII).
Secondo un'ulteriore aspetto della presente invenzione viene fornito un metodo per la sintesi di un composto presentante formula generale (I), come sopra definita, il metodo comprende una fase in cui un p-benzochinone avente formula generale (XII): According to a further aspect of the present invention, a method is provided for the synthesis of a compound having general formula (I), as defined above, the method comprises a step in which a p-benzoquinone having general formula (XII):
viene fatto reagire con un intermedio avente formula generale (XIII): is reacted with an intermediate having general formula (XIII):
in modo da ottenere composto presentante formula generale (I); R<1>, R<2>, R<3>, R<4>, R<5>, R<6>, R<7>, R<a>, z<1>, z<2>, sono definiti come sopra. so as to obtain compound having general formula (I); R <1>, R <2>, R <3>, R <4>, R <5>, R <6>, R <7>, R <a>, z <1>, z <2>, are defined as above.
Secondo alcune forme di attuazione il pbenzochinone avente formula generale (XII) viene ottenuto mediante una reazione di idrolisi del pbenzochinone avente formula generale (XIV): According to some embodiments, pbenzoquinone having general formula (XII) is obtained by means of a hydrolysis reaction of pbenzoquinone having general formula (XIV):
Vantaggiosamente, il p-benzochinone avente formula generale (XIV) viene ottenuto facendo reagire un p-benzochinone avente formula generale (XV): Advantageously, the p-benzoquinone having general formula (XIV) is obtained by reacting a p-benzoquinone having general formula (XV):
in cui LG è come sopra definito, con ulteriore intermedio avente formula generale (XVI): in which LG is as defined above, with a further intermediate having a general formula (XVI):
( ) ()
Vantaggiosamente, il p-benzochinone avente formula generale (XV) viene ottenuto facendo reagire la diammina avente formula generale (X): Advantageously, the p-benzoquinone having general formula (XV) is obtained by reacting the diamine having general formula (X):
(X) (X)
con un eccesso di un p-benzochinone avente formula generale (VII) : with an excess of a p-benzoquinone having general formula (VII):
(VII) (VII)
Secondo un'ulteriore aspetto della presente invenzione viene fornito il composto intermedio avente formula generale (VIII): According to a further aspect of the present invention, the intermediate compound having general formula (VIII) is provided:
in cui R<6>, R<7>, R<8>, Z<2>, sono definiti secondo una delle rivendicazioni da 1 a 32. wherein R <6>, R <7>, R <8>, Z <2>, are defined according to one of claims 1 to 32.
Secondo un'ulteriore aspetto della presente invenzione viene fornito il composto avente formula generale (VII): According to a further aspect of the present invention, the compound having general formula (VII) is provided:
in cui LG, R<1>, R<2>, R<3>, R<4>, R<5>, Z<1>sono definiti secondo una delle rivendicazioni da 1 a 32. wherein LG, R <1>, R <2>, R <3>, R <4>, R <5>, Z <1> are defined according to one of claims 1 to 32.
Ulteriori caratteristiche della presente invenzione risulteranno dalla descrizione che segue di alcuni esempi meramente illustrativi e non limitativi. Further characteristics of the present invention will emerge from the following description of some merely illustrative and non-limiting examples.
Esempi Examples
La caratterizzazione dei prodotti ottenuti è stata effettuata tramite diverse tecniche: The characterization of the products obtained was carried out using different techniques:
• spettroscopia di risonanza magnetica nucleare: • nuclear magnetic resonance spectroscopy:
gli spettri<1>HNMR sono stati registrati con strumenti Varian VXR 200 e 300 MHz. I valori di Chemical shift sono riportati in parti per milione (ppm) in relazione al tetrametilsilano (TMS). Le molteplicità sono riportate come: s (singoletto), d (doppietto), t (tripletto), q (quartetto), m (multipletto), m complex (multipletto complesso), br s (singoletto allargato), exch (scambiabile con D20); <1> HNMR spectra were recorded with Varian VXR 200 and 300 MHz instruments. Chemical shift values are reported in parts per million (ppm) in relation to tetramethylsilane (TMS). The multiplicities are reported as: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), m complex (complex multiplet), br s (extended singlet), exch (exchangeable with D20 );
• spettroscopia di massa: sono stati registrati sia spettri di massa ESI-MS realizzati con strumento waters Micromas ZQ4000, sia spettri EI-MS realizzati con strumento Finnigan MAT 95 XP. • mass spectroscopy: both ESI-MS mass spectra realized with the waters Micromas ZQ4000 instrument, and EI-MS spectra realized with Finnigan MAT 95 XP instrument were recorded.
Le reazioni sono state seguite tramite cromatografia su strato sottile (TLC) utilizzando lastre di gel di silice (Kieselgel 60, F2540.25 mm Merck) e visualizzate alla lampada ad UV o per esposizione ai vapori di iodio o con permanganato. The reactions were followed by thin layer chromatography (TLC) using silica gel plates (Kieselgel 60, F2540.25 mm Merck) and visualized under the UV lamp or by exposure to iodine vapor or permanganate.
Le purificazioni dei composti sono state eseguite tramite colonne cromatografiche flash (Kieselgel 40, 0.040-0.063mm) e a caduta (Kieselgel 60, 0.063-0.200mm). The purifications of the compounds were carried out by means of flash (Kieselgel 40, 0.040-0.063mm) and gravity (Kieselgel 60, 0.063-0.200mm) chromatographic columns.
I reagenti utilizzati sono stati acquistati presso Sigma Aldrich. The reagents used were purchased from Sigma Aldrich.
La nomenclatura delle strutture riportate è stata ottenuta con il programma CHEM-DRAW ULTRA. The nomenclature of the reported structures was obtained with the CHEM-DRAW ULTRA program.
Esempi 1-22 Examples 1-22
Per la sintesi dei composti 1-4 sottoriportati è stato seguito il seguente schema sintetico: For the synthesis of the compounds 1-4 reported below, the following synthetic scheme was followed:
Esempio 1 Example 1
N-(benzilossicarbonil) -esandiammina (5) N- (benzyloxycarbonyl) -hexanediamine (5)
Ad una soluzione di esandiammina (20 g 0.172 mol) in acqua (30 mi) in un pallone a tre colli, è stata aggiunta una punta di spatola di indicatore verde di bromocresolo e acido metansolfonico (23 mi, 0.33 mol), mantenendo il pH<5. La soluzione è stata diluita con etanolo (50 mi) ed agitata vigorosamente. To a solution of hexanediamine (20 g 0.172 mol) in water (30 ml) in a three-necked flask, a spatula tip of green indicator of bromcresol and methanesulfonic acid (23 ml, 0.33 mol) was added, maintaining the pH <5. The solution was diluted with ethanol (50ml) and vigorously stirred.
Una soluzione di benzilcloroformiato (8 mi 0.054 mol) in dimetossietano (25 mi) ed una soluzione al 50% di potassio acetato (20 mi) sono state introdotte contemporaneamente. La reazione è stata scaldata a 40°C in bagno di acqua calda e ed è stata lasciata in agitazione per Ih. Per evaporazione sottovuoto dei solventi si è ottenuta una sospensione gialla che è stata filtrata su buchner. La soluzione acquosa gialla è stata estratta con toluene (2 x 100 mi) e basificata con KOH in polvere, fino a raggiungere un pH=13. Si è estratto con toluene (2 x 150 mi). Gli estratti organici riuniti sono stati lavati con acqua (100 mi), anidrificati con Na2S04e concentrati sotto vuoto a dare 6.67 g di 5 sotto forma di olio. Resa 49%. A solution of benzyl chloroformate (8 ml 0.054 mol) in dimethoxyethane (25 ml) and a 50% solution of potassium acetate (20 ml) were introduced simultaneously. The reaction was heated to 40 ° C in a hot water bath and was left under stirring for 1 hour. By vacuum evaporation of the solvents a yellow suspension was obtained which was filtered on buchner. The yellow aqueous solution was extracted with toluene (2 x 100 ml) and basified with powdered KOH, until reaching a pH = 13. It was extracted with toluene (2 x 150ml). The combined organic extracts were washed with water (100 ml), dried with Na2SO4 and concentrated under vacuum to give 6.67 g of 5 in the form of oil. Yield 49%.
1H-NMR (CDC13, 200 MHz) δ 1.33 (s, 2H), δ 1.40-1.60 (m, 8H), δ 2.70 (t, 2H), δ 3.25 (q, 2H), δ 4.90 (br m, IH) , δ 5 . 05 (s , 2H) , δ 7.35 (s, 5H) . Esempio 2 1H-NMR (CDC13, 200 MHz) δ 1.33 (s, 2H), δ 1.40-1.60 (m, 8H), δ 2.70 (t, 2H), δ 3.25 (q, 2H), δ 4.90 (br m, IH ), δ 5. 05 (s, 2H), δ 7.35 (s, 5H). Example 2
N- (benzilossicarbonil)-propandiammina(6) N- (benzyloxycarbonyl) -propanediamine (6)
Il composto 6 è stato ottenuto dalla reazione tra propandiammina (10.9 mi, 0.13 mol) e acido metansolfonico (15.5 mi, 0.24 mol), seguendo la procedura descritta per 5 per dare 6.94 g di 6 con una resa del 30%. Compound 6 was obtained from the reaction between propanediamine (10.9 ml, 0.13 mol) and methanesulfonic acid (15.5 ml, 0.24 mol), following the procedure described for 5 to give 6.94 g of 6 with a yield of 30%.
1H-NMR (CDC13, 200 MHz) δ 1.33 (s, 2H), δ 1.58-1.67 (m, 2H), δ 2.78 (t, 2H), δ 3.30 (q, 2H), δ 5.11 (s, 2H), δ 5.38 (br m, 1H), δ 7.35 (s, 5H). 1H-NMR (CDC13, 200 MHz) δ 1.33 (s, 2H), δ 1.58-1.67 (m, 2H), δ 2.78 (t, 2H), δ 3.30 (q, 2H), δ 5.11 (s, 2H) , δ 5.38 (br m, 1H), δ 7.35 (s, 5H).
Esempio 3 Example 3
acido [6-(2-metossi-benzilamino)-esil] carbammico benzil estere (7) [6- (2-methoxy-benzylamino) -hexyl] carbamic acid benzyl ester (7)
Ad una soluzione di 5 (3.92 g 15.6 mmol) in toluene è stata aggiunta la metossibenzaldeide (2.13 g 15.7 mmol), mantenendo il tutto in agitazione. La reazione è stata scaldata a riflusso (T 140°C), allontanando l'acqua di reazione in un apparato di Dean-Stark, per 3.5h. Si è evaporato il solvente e l'olio rossastro che si è formato è stato ripreso con etanolo (50 mi). Successivamente è stato introdotto con cautela e a freddo NaBH4(0.6 g 15.8 mmol), lasciando il sistema in agitazione per tutta la notte a T ambiente. A freddo si è acidificata la miscela di reazione con HC1 al 37% e si è evaporato il solvente sotto vuoto. Si è lavato con etere (2 x 60 mi) il solido giallo-biancastro ottenuto, si è filtrato sotto vuoto e si è seccato alla pompa da vuoto, ottenendo 5 g di 7 sottoforma di cloridrato. Resa del 70%. Methoxybenzaldehyde (2.13 g 15.7 mmol) was added to a solution of 5 (3.92 g 15.6 mmol) in toluene, keeping everything stirred. The reaction was heated under reflux (T 140 ° C), removing the reaction water in a Dean-Stark apparatus, for 3.5h. The solvent was evaporated and the reddish oil which formed was taken up with ethanol (50 ml). Subsequently, NaBH4 (0.6 g 15.8 mmol) was introduced with caution and cold, leaving the system under stirring overnight at room T. When cold, the reaction mixture was acidified with 37% HC1 and the solvent was evaporated under vacuum. The obtained yellow-whitish solid was washed with ether (2 x 60 ml), filtered under vacuum and dried with a vacuum pump, obtaining 5 g of 7 in the form of hydrochloride. 70% yield.
<1>H-NMR (CDC13, 200 MHz) δ 1.30-1.80 (m, 8H) , δ 1. 80 (br m, 1H) , δ 2.78 (t , 2H) , δ 3 .17 (t, 2H) , δ 3 . 60 (s , 2H) , δ 3 . 85 (s , 3H) , δ 4. 90 (br m, IH) , δ 5 . 10 (s , 2H) , 6.89 (m, 2H) , δ 7.23 (d, 2H) , δ 7.28 (s , 5H) . <1> H-NMR (CDC13, 200 MHz) δ 1.30-1.80 (m, 8H), δ 1. 80 (br m, 1H), δ 2.78 (t, 2H), δ 3 .17 (t, 2H) , δ 3. 60 (s, 2H), δ 3. 85 (s, 3H), δ 4. 90 (br m, 1H), δ 5. 10 (s, 2H), 6.89 (m, 2H), δ 7.23 (d, 2H), δ 7.28 (s, 5H).
Esempio 4 Example 4
acido [6-(2-metossi-benzilamino)-propil] [6- (2-methoxy-benzylamino) -propyl] acid
carbammico benzil estere (8) carbamic benzyl ester (8)
il composto 8 è stato ottenuto dalla reazione tra 6 (3 g 14.4 mmol) e metossibenzaldeide (1.9 g 14.5 mmol). Si purifica con cromatografia flash, eluendo con CH2C12/CH3OH/NH3(9.5:0.5:0.05), per dare 1 g di 8, con resa del 21%. compound 8 was obtained from the reaction between 6 (3 g 14.4 mmol) and methoxybenzaldehyde (1.9 g 14.5 mmol). It is purified by flash chromatography, eluting with CH2C12 / CH3OH / NH3 (9.5: 0.5: 0.05), to give 1 g of 8, with a yield of 21%.
1H-NMR (CDCI3, 200 MHz) δ 1.73 (s, 2H), δ 2.7 (t, 2H), δ 3.32 (q, 2H), δ 3.78 (s, 2H), δ 3.83 (s, 3H), δ 5.11 (s, 2H), δ 5.73 (m, 1H), δ 6.89 (m, 2H), δ 7.23 (d, 2H), δ 7.28 (s, 5H). 1H-NMR (CDCI3, 200 MHz) δ 1.73 (s, 2H), δ 2.7 (t, 2H), δ 3.32 (q, 2H), δ 3.78 (s, 2H), δ 3.83 (s, 3H), δ 5.11 (s, 2H), δ 5.73 (m, 1H), δ 6.89 (m, 2H), δ 7.23 (d, 2H), δ 7.28 (s, 5H).
Esempio 5 Example 5
acido{6-etil- (2-metossi-benzil)-amino]-esil} carbammico benzil estere (9) {6-ethyl- (2-methoxy-benzyl) -amino] -hexyl} carbamic acid benzyl ester (9)
Una soluzione in metanolo di 7 (10.2 g 0.025 mol) cloridrato, è stata trattata con KOH. Successivamente è stata aggiunta acetaldeide (2.8 mi 0.05 mol), lasciando in agitazione per 30 minuti a t. a. Si è aggiunto NaCNBH3(0.6 g 9.6 mmol), lasciando in agitazione la miscela di reazione per tutta la notte. Si è basificato con KOH e si filtra su celite. Si è concentrata la soluzione filtrata e si è solubilizzato il solido giallo ottenuto con CH2C12(200 mi). Si è estratto con acqua (2 x 200 mi), si sono raccolti gli estratti organici, si anidrificano con Na2SO4e si concentrano sotto vuoto. Si è ottenuto un olio rossastro, che si è trattato con etere di petrolio (100 mi) sotto vigorosa agitazione e blando riscaldamento per 10 minuti. Si è interrotta l'agitazione, lasciando precipitare un solido giallastro. Si è ripetuta quest'ultima operazione tre volte, decantando sempre le soluzioni eteree, che sono state infine riunite e concentrate per ottenere 4.28g di prodotto etilato 9. Resa 43% A methanol solution of 7 (10.2 g 0.025 mol) hydrochloride was treated with KOH. Subsequently acetaldehyde (2.8 ml 0.05 mol) was added, leaving under stirring for 30 minutes at t. to. NaCNBH3 (0.6 g 9.6 mmol) was added, leaving the reaction mixture under stirring overnight. It is basified with KOH and is filtered on celite. The filtered solution was concentrated and the yellow solid obtained with CH 2 Cl 12 (200 ml) was solubilized. It was extracted with water (2 x 200 ml), the organic extracts were collected, dried with Na2SO4 and concentrated under vacuum. A reddish oil was obtained, which was treated with petroleum ether (100 ml) under vigorous stirring and gentle heating for 10 minutes. Stirring was stopped, leaving a yellowish solid to precipitate. This last operation was repeated three times, always decanting the ethereal solutions, which were finally combined and concentrated to obtain 4.28g of ethylated product 9. Yield 43%
<1>H-NMR (CDC13, 200 MHz) δ 1.07 (t, 3H), δ 1.20-1.60 (m, 8H), δ 2.30 (t, 2H), δ 2.57 (t, 2H), δ 3.17 (q, 2H), δ 3.60 (s, 2H), δ 3.90 (ε, 3H), δ 4.70-4.90 (m, IH), δ 5.15 (s, 2H), δ 6.89 (m, 2H), δ 7.23 (d, 2H), δ 7.28 (s, 5H). <1> H-NMR (CDC13, 200 MHz) δ 1.07 (t, 3H), δ 1.20-1.60 (m, 8H), δ 2.30 (t, 2H), δ 2.57 (t, 2H), δ 3.17 (q , 2H), δ 3.60 (s, 2H), δ 3.90 (ε, 3H), δ 4.70-4.90 (m, IH), δ 5.15 (s, 2H), δ 6.89 (m, 2H), δ 7.23 (d , 2H), δ 7.28 (s, 5H).
Esempio 6 Example 6
acido{6-etil- (2-metossi-benzil)-amino]-esil}carbammico benzil estere (10) {6-ethyl- (2-methoxy-benzyl) -amino] -hexyl} carbamic acid benzyl ester (10)
Il composto 10 è stato ottenuto da una soluzione di 8 (1 g 3 mmol) e acetaldeide (1 mi 6 mmol), per dare 0.8 g di 10, con resa del 78%. Compound 10 was obtained from a solution of 8 (1 g 3 mmol) and acetaldehyde (1 ml 6 mmol), to give 0.8 g of 10, with a yield of 78%.
δ 1.07 (t, 3H), δ 1.20-1.60 (m, 2H), δ 2.30 (t, 2H), 62.57 (t, 2H), δ 3.17 (q, 2H), δ 3.60 (s, 2H), δ 3.90 (s, 3H), δ 4.70-4.90 (m, IH), δ 5.15 (s, 2H), δ 6.89 (m, 2H), δ 7.23 (d, 2H), δ 7.28 (s, 5H). δ 1.07 (t, 3H), δ 1.20-1.60 (m, 2H), δ 2.30 (t, 2H), 62.57 (t, 2H), δ 3.17 (q, 2H), δ 3.60 (s, 2H), δ 3.90 (s, 3H), δ 4.70-4.90 (m, IH), δ 5.15 (s, 2H), δ 6.89 (m, 2H), δ 7.23 (d, 2H), δ 7.28 (s, 5H).
Esempio 7 Example 7
N<1>-etil- N<1>-(2-metossi-benzil)-1,6-diamminoesano (11) N <1> -ethyl- N <1> - (2-methoxy-benzyl) -1,6-diaminohexane (11)
Si è solubilizzato 9 (3.7 g 9.3 mmol) in acido acetico (50 mi) e si è aggiunta una soluzione di HBr/CH3C00H (10 ml), lasciando in agitazione a T ambiente per 6h. Si è aggiunto etere (70 ml) e si è lasciato in agitazione per tutta la notte a τ ambiente. Si sono formati un olio scuro e una soluzione, che viene decantata. Si è ripreso l'olio, con acqua (70 ml) e si è estratto con CH2C12(3 x 70ml ). Si è basificata la soluzione acquosa con KOH fino a pH=10, che è stata estratta con CH2C12(3 x 100ml). Gli estratti organici riuniti sono stati anidrificati, evaporati e purificati per cromatografia flash. Eluendo con CH2C12/Toluene/CH30H/NH3(8:0.5:1.5:0.15) è stato ottenuto 1 g di olio giallo-marrone. Resa 41%. 9 was solubilized (3.7 g 9.3 mmol) in acetic acid (50 ml) and a solution of HBr / CH3C00H (10 ml) was added, stirring at room T for 6h. Ether (70 ml) was added and it was left under stirring overnight at room τ. A dark oil and a solution have formed, which is decanted. The oil was taken up with water (70 ml) and extracted with CH2C12 (3 x 70ml). The aqueous solution was basified with KOH up to pH = 10, which was extracted with CH2C12 (3 x 100ml). The combined organic extracts were dried, evaporated and purified by flash chromatography. 1 g of yellow-brown oil was obtained by eluting with CH2C12 / Toluene / CH30H / NH3 (8: 0.5: 1.5: 0.15). Yield 41%.
<1>H-NMR (CDC13, 200 MHz) δ 1. 07 (t, 3H) , δ 1.32 (s , 2H) , δ 1.47-1. 52 (m, 8H) , δ 2.50 (m, 4H) , δ 2.68 (t, 2H) , δ 3 .61 (s , 2H) , δ 3 .83 (s , 3H) , δ 6. 84-6. 94 (m, 2H) , δ 7.24 (t , IH) , δ 7.41 (dfIH) . <1> H-NMR (CDC13, 200 MHz) δ 1. 07 (t, 3H), δ 1.32 (s, 2H), δ 1.47-1. 52 (m, 8H), δ 2.50 (m, 4H), δ 2.68 (t, 2H), δ 3 .61 (s, 2H), δ 3 .83 (s, 3H), δ 6. 84-6. 94 (m, 2H), δ 7.24 (t, 1H), δ 7.41 (dfIH).
Esempio 8 Example 8
N<1>-etil- N<1>-(2-metossi-benzil)-1,3-diamminopropano (12) N <1> -ethyl- N <1> - (2-methoxy-benzyl) -1,3-diaminopropane (12)
Il composto 12 è stato ottenuto da una soluzione di 10 (0.8 g 2 mmol) e HBr/CH3COOH (2 ml), per dare 0.5 g di 12, con resa del 83%. Compound 12 was obtained from a solution of 10 (0.8 g 2 mmol) and HBr / CH3COOH (2 ml), to give 0.5 g of 12, with a yield of 83%.
<1>H-NMR (CDCI3, 200 MHz) δ 1.07 (t, 3H), δ 1.50 (s, 2H) δ 1.57-1.71 (m, 5H), δ 2.49-2.60 (m, 4H), δ 2.73 (t, 2H), δ 3.59 (s, 2H), δ 3.83 (s, 3H), δ 6.85-6.98 (m, 2H), δ 7.23 (t, IH), δ 7.41 (d, IH). <1> H-NMR (CDCI3, 200 MHz) δ 1.07 (t, 3H), δ 1.50 (s, 2H) δ 1.57-1.71 (m, 5H), δ 2.49-2.60 (m, 4H), δ 2.73 ( t, 2H), δ 3.59 (s, 2H), δ 3.83 (s, 3H), δ 6.85-6.98 (m, 2H), δ 7.23 (t, IH), δ 7.41 (d, IH).
Esempio 9 Example 9
2 - {6- [etil- (-2 -metossi-benzil) -araminoesano} -5-metossi- [1, 4] benzochinone (13 ) 2 - {6- [ethyl- (-2 -methoxy-benzyl) -araminohexane} -5-methoxy- [1, 4] benzoquinone (13)
Con una vigorosa agitazione e a caldo (T 80°C), si è solubilizzato un eccesso di 2,5-dimetossi-l,4benzochinone (0.80 g 4.7 mmol) in etanolo (150 mi) e cloroformio (50 mi) per circa Ih. Si è aggiunto quindi goccia a goccia una soluzione di diammina 11 (0.180 g 0.168 mmol), in CHCI3(10 ml). Si è osservato un progressivo viraggio di colore dal giallo all'arancio-rosso. Si è lasciata andare la reazione in agitazione per tutta la notte a T ambiente. Si è filtrato con buchner il chinone in eccesso non reagito e si sono evaporati i solventi sotto vuoto, il residuo ottenuto è stato purificato tramite cromatografia a caduta. Eluendo con CH2C12/CH30H/NH3(9.5:0.5:0.05), si sono ottenuti 70 mg di 13. Resa 26%. With vigorous stirring and under heat (T 80 ° C), an excess of 2,5-dimethoxy-1,4benzoquinone (0.80 g 4.7 mmol) in ethanol (150 ml) and chloroform (50 ml) was solubilized for about 1 h. A solution of diamine 11 (0.180 g 0.168 mmol), in CHCl3 (10 ml) was then added dropwise. A progressive color change from yellow to orange-red was observed. The reaction was allowed to go under stirring overnight at room temperature. The unreacted excess quinone was filtered with buchner and the solvents were evaporated under vacuum, the residue obtained was purified by drop chromatography. Eluting with CH2C12 / CH30H / NH3 (9.5: 0.5: 0.05), 70 mg of 13 were obtained. Yield 26%.
<1>H-NMR (CD1I3, 300 MHz) δ 1.07 (t, 3H), δ 1.29-1.45 (m, 8H), δ 2.40-2.60 (m, 4H), δ 3.11 (q, 2H), δ 3.61 (s, 2H), δ 3.83 (s, 3H), δ 3.85 (s, 3H), δ 5.62 (S, 1H), δ 5.79 (s, 1H), 5.90-6.00 (m, 1H), δ 6.84-6.94 (m, 2H), δ 7.24 (t, 1H), δ 7.45 (d, 1H). <1> H-NMR (CD1I3, 300 MHz) δ 1.07 (t, 3H), δ 1.29-1.45 (m, 8H), δ 2.40-2.60 (m, 4H), δ 3.11 (q, 2H), δ 3.61 (s, 2H), δ 3.83 (s, 3H), δ 3.85 (s, 3H), δ 5.62 (S, 1H), δ 5.79 (s, 1H), 5.90-6.00 (m, 1H), δ 6.84- 6.94 (m, 2H), δ 7.24 (t, 1H), δ 7.45 (d, 1H).
Esempio 10 Example 10
2-{3- [etil- (2-metossi-benzile) -aminopropano] -5-metossi- [1,4] -benzochinone (14) 2- {3- [ethyl- (2-methoxy-benzyl) -aminopropane] -5-methoxy- [1,4] -benzoquinone (14)
Il composto 14 è stato ottenuto da 2,5-dimetossi-1,4-benzochinone (2.12 g 12.6 mmol) e da 12 (0.4 g 1.8 mmol). Si è purificato con una cromatografia flash CH2C12/CH3OH/NH3(9.75:0.25:0.025), ottenendo 0.25g di 14 con una resa del 40%. Compound 14 was obtained from 2,5-dimethoxy-1,4-benzoquinone (2.12 g 12.6 mmol) and from 12 (0.4 g 1.8 mmol). It was purified with a flash chromatography CH2C12 / CH3OH / NH3 (9.75: 0.25: 0.025), obtaining 0.25g of 14 with a yield of 40%.
<1>H-NMR (CDC13, 300 MHz) δ 1.12 (t, 3H), δ 1.82 (m, 2H), δ 2.58 (m, 4H), δ 3.15 (q, 2H), δ 3.63 (s, 2H) , δ 3.82 (s, 3H), δ 3.87 (s, 3H), δ 5.32 (s, 1H), δ 5.36 (s, 1H), δ 5.75 (s, 1H), δ 6.84-6.94 (m, 2H), δ 7.24 (t, 1H), δ 7.42 (d, 1H). <1> H-NMR (CDC13, 300 MHz) δ 1.12 (t, 3H), δ 1.82 (m, 2H), δ 2.58 (m, 4H), δ 3.15 (q, 2H), δ 3.63 (s, 2H ), δ 3.82 (s, 3H), δ 3.87 (s, 3H), δ 5.32 (s, 1H), δ 5.36 (s, 1H), δ 5.75 (s, 1H), δ 6.84-6.94 (m, 2H ), δ 7.24 (t, 1H), δ 7.42 (d, 1H).
Esempio 11 Example 11
[3-(4-{6- [etil- (2-metossi-benzil) -amino] -aminoesano} -3 ,6-diossi- 1,4-dienilamino-cicloesano) -propil] -acido carbammico ter-butil estere (15) [3- (4- {6- [ethyl- (2-methoxy-benzyl) -amino] -aminohexane} -3,6-dioxy- 1,4-dienylamino-cyclohexane) -propyl] -carbamic acid tert-butyl ester (15)
Ad una soluzione di 13 (0.08 g 2 mmol) in CH2C12(5 mi), si è aggiunto N- (ter-butossicarbonil) -1,3-propandiammina (commerciale) (0.035 g 2 mmol), in diclorometano . Si è lasciata la reazione in agitazione tutta la notte a T ambiente. Il solvente è stato evaporato sotto vuoto e si è purificato il prodotto grezzo ottenuto attraverso cromatografia flash. Eluendo con CH2CI2/CH3OH/NH3(9.5:0.5:0.05), si sono ottenuti 0.08g di 15, con una resa del 73%. To a solution of 13 (0.08 g 2 mmol) in CH2C12 (5 ml), N- (tert-butoxycarbonyl) -1,3-propanediamine (commercial) (0.035 g 2 mmol), in dichloromethane, was added. The reaction was left under stirring overnight at room temperature. The solvent was evaporated under vacuum and the crude product obtained was purified by flash chromatography. Eluting with CH2CI2 / CH3OH / NH3 (9.5: 0.5: 0.05), 0.08g of 15 were obtained, with a yield of 73%.
<1>H-NMR (CDC13, 300 MHz) δ 1.11 (t, 3H), δ 1.48 (S, 9H), δ 1.64 (m, 8H), δ 1.83-1.88 (m, 2H), δ 2.52 (m, 4H), δ 3.17 (q, 6H), δ 3.63 (s, 2H), δ 3.85 (s, 3H) , δ 4.69 (m, 1H), δ 5.32 (s, 1H), δ 5.33 (s, 1H), δ 5.34 (s, 1H), δ 6.59 (m, 1H), δ 6.84-6.94 (m, 2H), δ 7.24 (t, 1H), δ 7.43 (d, 1H). <1> H-NMR (CDC13, 300 MHz) δ 1.11 (t, 3H), δ 1.48 (S, 9H), δ 1.64 (m, 8H), δ 1.83-1.88 (m, 2H), δ 2.52 (m , 4H), δ 3.17 (q, 6H), δ 3.63 (s, 2H), δ 3.85 (s, 3H), δ 4.69 (m, 1H), δ 5.32 (s, 1H), δ 5.33 (s, 1H ), δ 5.34 (s, 1H), δ 6.59 (m, 1H), δ 6.84-6.94 (m, 2H), δ 7.24 (t, 1H), δ 7.43 (d, 1H).
Esempio 12 Example 12
[6-(4-{3-etil-(2-metossi-benzil)-amino]-propilamino}-3,6-diossi-cicloesa-l, 4-dienilamino)-esil]-acido carbammico ter-butil estere (16) [6- (4- {3-ethyl- (2-methoxy-benzyl) -amino] -propylamino} -3,6-dioxy-cyclohexa-1,4-dienylamino) -hexyl] -carbamic acid tert-butyl ester ( 16)
Il conposto 16 è stato ottenuto dalla reazione tra 14 {0.1209 3.3 mmol) e N-(ter-butossicarbonil)-1,6-esandiammina (commerciale) {0.070 g, 3.3 mmol), seguendo la procedura descritta per 15. (Resa 84%). Compound 16 was obtained from the reaction between 14 {0.1209 3.3 mmol) and N- (tert-butoxycarbonyl) -1,6-hexanediamine (commercial) {0.070 g, 3.3 mmol), following the procedure described for 15. (Yield 84 %).
<1>H-NMR (CDC13, 200 MHz) δ 1.12 (t, 3H), δ 1.48 (s, 9H), δ 1.67 (m, 8H), δ 1.81-1.88 (m, 2H), δ 2.58 (m, 4H), δ 3.14 (q, 6H), δ 3.62 (s, 2H), δ 3.82 (s, 3H), δ 4.52 (m, 1H), δ 5.27 (s, IH), δ 5.29 (s, 1H), δ 5.32 (s, 1H), δ 6.57 (m, 1H), δ 6.86-6.99 (m, 2H), δ 7.24 {t, 1H), δ 7.41 (d, 1H). <1> H-NMR (CDC13, 200 MHz) δ 1.12 (t, 3H), δ 1.48 (s, 9H), δ 1.67 (m, 8H), δ 1.81-1.88 (m, 2H), δ 2.58 (m , 4H), δ 3.14 (q, 6H), δ 3.62 (s, 2H), δ 3.82 (s, 3H), δ 4.52 (m, 1H), δ 5.27 (s, IH), δ 5.29 (s, 1H ), δ 5.32 (s, 1H), δ 6.57 (m, 1H), δ 6.86-6.99 (m, 2H), δ 7.24 {t, 1H), δ 7.41 (d, 1H).
Esempio 13 Example 13
[3-(4-{3-etil- (2-metossi-benzil)-amino]-propilamino}-3,6-diossi-cicloesil] -1,4-dienilamino)-propil]-acido carbammico ter-butil estere (17) [3- (4- {3-ethyl- (2-methoxy-benzyl) -amino] -propylamino} -3,6-dioxy-cyclohexyl] -1,4-dienylamino) -propyl] -carbamic acid tert-butyl ester (17)
Il conposto 17 è stato ottenuto dalla reazione tra 14 (0.125 g 3.5 mmol) e N-(ter-butossicarbonil)-1,3-propandiammina (commerciale) (0.060 g 3.5 mmol), seguendo la procedura descritta per 15. (Resa del 91%). Compound 17 was obtained from the reaction between 14 (0.125 g 3.5 mmol) and N- (tert-butoxycarbonyl) -1,3-propanediamine (commercial) (0.060 g 3.5 mmol), following the procedure described for 15. (Yield of 91%).
<1>H-NMR (CDC13, 200 MHz) δ 1.12 (t, 3H), δ 1.47 (s, 9H), δ 1.81-1.91 (m, 4H), δ 2.58 (m, 4H), δ 3.20 (q, 6H) , δ 3 .63 (s , 2H) , 6 3 .82 (s , 3H) , δ 4.62 (m, IH) , δ 5.27 (S , 1H) , δ 5 .30 (S , 1H) , δ 5.32 (s , 1H) , δ 6. 71 (m, 1H) , δ 6. 86-6.99 (m, 2H) , δ 7.24 {t, 1H) , δ 7.41 (d, 1H) . <1> H-NMR (CDC13, 200 MHz) δ 1.12 (t, 3H), δ 1.47 (s, 9H), δ 1.81-1.91 (m, 4H), δ 2.58 (m, 4H), δ 3.20 (q , 6H), δ 3 .63 (s, 2H), 6 3 .82 (s, 3H), δ 4.62 (m, 1H), δ 5.27 (S, 1H), δ 5 .30 (S, 1H), δ 5.32 (s, 1H), δ 6. 71 (m, 1H), δ 6. 86-6.99 (m, 2H), δ 7.24 {t, 1H), δ 7.41 (d, 1H).
Esempio 14 Example 14
[6-(4-{3-etil-(2-metossi-benzil)-amino]-esilamino}-3,6-diossi-ciloesa-1,4-dienilamino) -esil]-acido carbammico ter-butil estere (18) [6- (4- {3-ethyl- (2-methoxy-benzyl) -amino] -hexylamino} -3,6-dioxy-kylohexa-1,4-dienylamino) -hexyl] -carbamic acid tert-butyl ester ( 18)
Il composto 18 è stato ottenuto dalla reazione tra 13 (70 mg 1.7 mmol) e N-(ter-butossicarbonil)-1,6-esandiammina (commerciale) (37 mg 1.7 mmol), seguendo la procedura descritta per 15. (Resa del 42%). Compound 18 was obtained from the reaction between 13 (70 mg 1.7 mmol) and N- (tert-butoxycarbonyl) -1,6-hexanediamine (commercial) (37 mg 1.7 mmol), following the procedure described for 15. (Yield of 42%).
<1>-NMR (CDC13, 300 MHz) δ 1.16 (t, 3H), δ 1.28-1.51 (m, 16H), δ 1.67 (s, 9H), δ 2.59 (m, 4H), δ 3.18 (q, 6H), δ 3.72 (S, 2H), δ 3.86 (s, 3H), δ 4.54 (mfIH), δ 5.32 (s, 2H), δ 6.61-6.63 (ra, 2H), δ 6.89-6.99 (m, 2H), δ 7.24 (t, 1H), δ 7.52 (d, 1H). <1> -NMR (CDC13, 300 MHz) δ 1.16 (t, 3H), δ 1.28-1.51 (m, 16H), δ 1.67 (s, 9H), δ 2.59 (m, 4H), δ 3.18 (q, 6H), δ 3.72 (S, 2H), δ 3.86 (s, 3H), δ 4.54 (mfIH), δ 5.32 (s, 2H), δ 6.61-6.63 (ra, 2H), δ 6.89-6.99 (m, 2H), δ 7.24 (t, 1H), δ 7.52 (d, 1H).
Esempio 15 Example 15
2-(3-amino-propilamino) -5-{6-[etil-(2-metossibenzil)-amino]-aminoesil}- [1,4]-benzochinone (19) 2- (3-amino-propylamino) -5- {6- [ethyl- (2-methoxybenzyl) -amino] -aminohexyl} - [1,4] -benzoquinone (19)
Ad una soluzione rossa di 15 (0.08 g 1.5 mmol) in CH2CI2(5 mi), si è aggiunto a freddo CF3COOH (1 mi 13 mmol). Si è lasciato in agitazione per 1 h, quindi si è basificato con una soluzione satura di K2CO3e le due fasi risultanti sono state separate. L'estratto organico è stato anidrificato con Na2SO4anidro ed il solvente è stato evaporato sotto vuoto per dare 0.06g di 19, con una resa del 90%. To a red solution of 15 (0.08 g 1.5 mmol) in CH2CI2 (5 ml), CF3COOH (1 ml 13 mmol) was added cold. It was left under stirring for 1 h, then it was basified with a saturated solution of K2CO3 and the two resulting phases were separated. The organic extract was dried with anhydrous Na2SO4 and the solvent was evaporated under vacuum to give 0.06g of 19, with a yield of 90%.
<1>-NMR (CDC13, 200 MHz) δ 1.07 (t, 3H), δ 1.27 (S, 2H), δ 1.54-1.64 (m, 8H), δ 1.74-1.87 (m, 2H), δ 2.42-2.60 (m, 4H), δ 2.87 (t, 2H), δ 3.13 (q, 2H), δ 3.27 (q, 2Ξ), δ 3.59 (s, 2H), δ 3.83 (s, 3H), δ 5.30 (s, 1H), δ 5.32 (s, 1H), δ 6.59 (m, 1H), δ 6.89-6.99 (m, 2H), δ 7.24 (t, 1H), δ 7.43 (d, 1H). <1> -NMR (CDC13, 200 MHz) δ 1.07 (t, 3H), δ 1.27 (S, 2H), δ 1.54-1.64 (m, 8H), δ 1.74-1.87 (m, 2H), δ 2.42- 2.60 (m, 4H), δ 2.87 (t, 2H), δ 3.13 (q, 2H), δ 3.27 (q, 2Ξ), δ 3.59 (s, 2H), δ 3.83 (s, 3H), δ 5.30 ( s, 1H), δ 5.32 (s, 1H), δ 6.59 (m, 1H), δ 6.89-6.99 (m, 2H), δ 7.24 (t, 1H), δ 7.43 (d, 1H).
Esempio 16 Example 16
2- (6-amino-esilamino) - 5 - {3 - [etil- (2-metossibenzil) -amino] -propilamino } - [1, 4] -benzochinone (20) Il composto 20 è stato ottenuto dalla reazione tra 16 (0.150 g 2.7 mmol) e CF3C00H (2 mi 26 mmol), seguendo la procedura descritta per 19. (Resa del 96%). 2- (6-amino-hexylamino) - 5 - {3 - [ethyl- (2-methoxybenzyl) -amino] -propylamino} - [1, 4] -benzoquinone (20) Compound 20 was obtained from the reaction between 16 (0.150 g 2.7 mmol) and CF3C00H (2 ml 26 mmol), following the procedure described for 19. (96% yield).
<1>H-NMR (CDC13, 300 MHz) 61.11 (t, 3H), δ 1.28 (s, 2H), δ 1.69-1.80 (m, 10H), δ 2.54-2.61 (m, 4H), δ 2.75 (t, 2H), δ 3.18 (q, 2H), δ 3.27 (q, 2H), δ 3.63 (s, 2H), δ 3.83 (s, 3H), δ 5.29 (s, IH), δ 5.31 (s, 1H), δ 6.63 (m, 2H), δ 6.87-6.90 (m, 2H), δ 7.24 (t, 1H), δ 7.43 (d, 1H). <1> H-NMR (CDC13, 300 MHz) 61.11 (t, 3H), δ 1.28 (s, 2H), δ 1.69-1.80 (m, 10H), δ 2.54-2.61 (m, 4H), δ 2.75 ( t, 2H), δ 3.18 (q, 2H), δ 3.27 (q, 2H), δ 3.63 (s, 2H), δ 3.83 (s, 3H), δ 5.29 (s, IH), δ 5.31 (s, 1H), δ 6.63 (m, 2H), δ 6.87-6.90 (m, 2H), δ 7.24 (t, 1H), δ 7.43 (d, 1H).
Esempio 17 Example 17
2-(3-amino-propilamino) -5-{3-[etil-(2-metossibenzil)-amino]-propilamino} -[1,4]-benzochinone (21) Il composto 21 è stato ottenuto dalla reazione tra 17 (0.1 g 2 mmol) e CF3COOH (1 ml 13 mmol), seguendo la procedura descritta per 19. (Resa del 87%). 2- (3-amino-propylamino) -5- {3- [ethyl- (2-methoxybenzyl) -amino] -propylamino} - [1,4] -benzoquinone (21) Compound 21 was obtained from the reaction between 17 (0.1 g 2 mmol) and CF3COOH (1 ml 13 mmol), following the procedure described for 19. (87% yield).
<1>H-NMR (CDC13, 300 MHz) δ 1.11 (t, 3H), δ 1.30 (s, 2H), δ 1.69-1.80 (m, 4H), δ 2.54-2.61 (m, 4H), δ 2.75 (t, 2H), δ 3.18 (q, 2H), δ 3.28 (q, 2H), δ 3.63 (s, 2H), δ 3.83 (S, 3H), δ 5.25 (s, 1H), δ 5.31 (s, 1H), δ 6.63 (m, 2H), δ 6.87-6.90 (m, 2H), δ 7.24 (t, 1H), δ 7.43 (d, 1H). <1> H-NMR (CDC13, 300 MHz) δ 1.11 (t, 3H), δ 1.30 (s, 2H), δ 1.69-1.80 (m, 4H), δ 2.54-2.61 (m, 4H), δ 2.75 (t, 2H), δ 3.18 (q, 2H), δ 3.28 (q, 2H), δ 3.63 (s, 2H), δ 3.83 (S, 3H), δ 5.25 (s, 1H), δ 5.31 (s , 1H), δ 6.63 (m, 2H), δ 6.87-6.90 (m, 2H), δ 7.24 (t, 1H), δ 7.43 (d, 1H).
Esempio 18 Example 18
2-(6-amino-esclamino) -5-{6-[etil-(2-metossibenzil)-amino]-aminoesil} -[1,4]-benzochinone (22) 2- (6-amino-exclamine) -5- {6- [ethyl- (2-methoxybenzyl) -amino] -aminohexyl} - [1,4] -benzoquinone (22)
Il composto 22 è stato ottenuto dalla reazione tra 18 (0.04 g 0.74 mmol) e CF3COOH (0.7 ml 9 mmol), seguendo la procedura descritta per 19. (Resa del 97%). Compound 22 was obtained from the reaction between 18 (0.04 g 0.74 mmol) and CF3COOH (0.7 ml 9 mmol), following the procedure described for 19. (yield 97%).
<1>H-NMR (CDC13, 200 MHz) δ 1.12 (t, 3H), δ 1.27 (s, 2H), δ 1.43-1.47 (m, 16H), δ 2.42-2.61 (m, 4H), δ 2.87 (t, 2H), δ 3.18 (q, 2H), δ 3.27 (q, 2H), δ 3.63 (s, 2H), δ 3.90 (s, 3H), δ 5.30 (s, 1H), δ 5.32 (s, 1H), δ 6.60 (m, 2H), δ 6.94-6.98 (m, 2H), δ 7.25 (t, IH) , δ 7.43 (d, IH) . <1> H-NMR (CDC13, 200 MHz) δ 1.12 (t, 3H), δ 1.27 (s, 2H), δ 1.43-1.47 (m, 16H), δ 2.42-2.61 (m, 4H), δ 2.87 (t, 2H), δ 3.18 (q, 2H), δ 3.27 (q, 2H), δ 3.63 (s, 2H), δ 3.90 (s, 3H), δ 5.30 (s, 1H), δ 5.32 (s , 1H), δ 6.60 (m, 2H), δ 6.94-6.98 (m, 2H), δ 7.25 (t, IH), δ 7.43 (d, IH).
Esempio 19 Example 19
5- [1, 2] acido-di tio-3-pentanoico [3 - (4- {6- [etil- (2-metossi-benzil) -animino] -animino e sano} -3, 6-diossicicloesano-1, 4-dienilammino ) -propil] -amide (1) 5- [1, 2] thio-3-pentanoic acid-[3 - (4- {6- [ethyl- (2-methoxy-benzyl) -animino] -animino and healthy} -3, 6-dioxycyclohexane-1 , 4-dienylamino) -propyl] -amide (1)
Ad una soluzione di LA {0.035 g 0.17 mmol) in CH2C12(5 ml), lavorando al riparo dalla luce, si sono aggiunti in successione: una soluzione di 19 (0.06 g 0.135 mmol) in CH2CI2(5 ml), trietilammina (60 μl), idrossibenzotriazolo (0.035 g 0.26 mmol ), EDCI (1-etil-3-[3-(dimetilamino)propil]-carbodiimidecloridrato) (0.088 g 0.46 mol) e nuovamente trietilammina (60 μl). Si è lasciata la reazione in agitazione per tutta la notte a T ambiente. Si è estratto con acqua e si sono riuniti gli estratti organici, che sono stati anidrificati con Na2SO4anidro. Si è evaporato il solvente sotto vuoto e si è purificato il grezzo ottenuto tramite cromatografia a caduta. Eluendo con CH2CI2/CH3OH/NH3(9.5:0.5:0.05), si sono ottenuti 0.065 g di 1, con una resa del 75%. To a solution of LA {0.035 g 0.17 mmol) in CH2C12 (5 ml), working away from light, were added in succession: a solution of 19 (0.06 g 0.135 mmol) in CH2CI2 (5 ml), triethylamine (60 μl), hydroxybenzotriazole (0.035 g 0.26 mmol), EDCI (1-ethyl-3- [3- (dimethylamino) propyl] -carbodiimidechydrochloride) (0.088 g 0.46 mol) and again triethylamine (60 μl). The reaction was left under stirring overnight at room temperature. It was extracted with water and the organic extracts were combined, which were dried with Na2SO4 anhydrous. The solvent was evaporated under vacuum and the crude obtained was purified by drop chromatography. Eluting with CH2CI2 / CH3OH / NH3 (9.5: 0.5: 0.05), 0.065 g of 1 were obtained, with a yield of 75%.
ESI-MS: m/z: 631 [M+H<+>] ESI-MS: m / z: 631 [M + H <+>]
1H-NMR (CDC13, 200 MHz) δ 1.09 (t, 3H) , δ 1.27-1.33 (m, 10H) , δ 1.83-2.01 (m, 4H) , δ 2.22 (t, 2H) , δ 2.33 (t, 2H) , δ 2.43-2.53 (m, 4H) , δ 3.12-3.25 (m, 6H) , δ 3.34 (q, 2H) , δ 3.59 (tf2H) , δ 3.66 (m, IH), δ 3.69 (S, 2H) , δ 3.84 (s, 3Η) , δ 5.31 (s, 2H) , δ 5.58 (t, IH), δ 6.57 (t, IH), δ 6.85-6.89 (m, 2H) , δ 6.97 (t, IH) , δ 7.43 (d, IH) . 1H-NMR (CDC13, 200 MHz) δ 1.09 (t, 3H), δ 1.27-1.33 (m, 10H), δ 1.83-2.01 (m, 4H), δ 2.22 (t, 2H), δ 2.33 (t, 2H), δ 2.43-2.53 (m, 4H), δ 3.12-3.25 (m, 6H), δ 3.34 (q, 2H), δ 3.59 (tf2H), δ 3.66 (m, IH), δ 3.69 (S, 2H), δ 3.84 (s, 3Η), δ 5.31 (s, 2H), δ 5.58 (t, IH), δ 6.57 (t, IH), δ 6.85-6.89 (m, 2H), δ 6.97 (t, 1H), δ 7.43 (d, 1H).
Esempio 20 Example 20
5- [1,2]acido-ditio-3-pentanoico [6- (4-{3- [etil-(2-metossi-benzil) -amino] - }-3, 6-diossicicloesano-1, 4-dienilaminino) -esil] -amide (2) 5- [1,2] -dithio-3-pentanoic acid [6- (4- {3- [ethyl- (2-methoxy-benzyl) -amino] -} -3, 6-dioxycyclohexane-1,4-dienylaminino ) -hexyl] -amide (2)
Il composto 2 è stato ottenuto dalla reazione tra LA (0.066 g 0.32 mmol) e 20 (0.130 g 0.3 mmol) , aggiungendo trietilammina ( 100μl ) idrossibenzotriazolo (0.035 g 0.26 mmol), EDC1 (0.17 g 0.87 mmol) e nuovamente trietilammina (100 μl) seguendo la procedura descritta per 1 per dare 0.07 g di 2 con una resa del 37%. Compound 2 was obtained from the reaction between LA (0.066 g 0.32 mmol) and 20 (0.130 g 0.3 mmol), adding triethylamine (100μl) hydroxybenzotriazole (0.035 g 0.26 mmol), EDC1 (0.17 g 0.87 mmol) and again triethylamine (100 μl) following the procedure described for 1 to give 0.07 g of 2 with a yield of 37%.
ESI -MS : m/z: 631 [M+H<+>] ESI -MS: m / z: 631 [M + H <+>]
<1>H-NMR (CDC13, 200 MHz) δ 1.14 (t, 3H), δ 1.41-1.62 (m, 10H), δ 1.88-2.01 (m, 4H), δ 2.19 (t, 2H), δ 2.43 (t, 2H), δ 2.49-2.60 (m, 4H), δ 3.12-3.21 (m, 6H) , δ 3.29 (q, 2H) , δ 3.61 (t, 2H) , δ 3.66 (m, 1H) , δ 3.69 (s, 2H) , δ 3.83 (s, 3H) , δ 5.27 (S, 1H), δ 5.29 (S, IH), δ 5.48 (t, IH), δ 6.58 (t, 1H) , δ 6.85-6.89 (m, 2H) , δ 6.97 {t, IH), δ 7.40 (d, 1H) . <1> H-NMR (CDC13, 200 MHz) δ 1.14 (t, 3H), δ 1.41-1.62 (m, 10H), δ 1.88-2.01 (m, 4H), δ 2.19 (t, 2H), δ 2.43 (t, 2H), δ 2.49-2.60 (m, 4H), δ 3.12-3.21 (m, 6H), δ 3.29 (q, 2H), δ 3.61 (t, 2H), δ 3.66 (m, 1H), δ 3.69 (s, 2H), δ 3.83 (s, 3H), δ 5.27 (S, 1H), δ 5.29 (S, IH), δ 5.48 (t, IH), δ 6.58 (t, 1H), δ 6.85 -6.89 (m, 2H), δ 6.97 {t, 1H), δ 7.40 (d, 1H).
Esempio 21 Example 21
5-[1,2]acido-ditio-3-pentanoico[3-(4-{3-[etil-(2-metossi-benzil)-ammano]-aminopropano}-3,6-diossicicloesano-1,4-dienilammino)-propil]-amide (3) 5- [1,2] -dithio-3-pentanoic acid [3- (4- {3- [ethyl- (2-methoxy-benzyl) -amane] -aminopropane} -3,6-dioxycyclohexane-1,4- dienylamino) -propyl] -amide (3)
Il composto 3 è stato ottenuto dalla reazione tra LA (0.038 g 0.186 mmol) e 21 (0.07 g 0.17 mmol ), aggiungendo trietilammina (60μl) , idrossibenzotriazolo (0.038 g 0.28 mmol), BDC1 (0.096 g 0.5 mmol) e di nuovo trietilammina (60μl) seguendo la procedura descritta per 1 per dare 0.0 7g di 3 con una resa del 70%. Compound 3 was obtained from the reaction between LA (0.038 g 0.186 mmol) and 21 (0.07 g 0.17 mmol), adding triethylamine (60μl), hydroxybenzotriazole (0.038 g 0.28 mmol), BDC1 (0.096 g 0.5 mmol) and again triethylamine (60μl) following the procedure described for 1 to give 0.0 7g of 3 with a yield of 70%.
ESI-MS: m/z: 58 9 [M+H<+>] ESI-MS: m / z: 58 9 [M + H <+>]
<1>H-NMR (CDC13, 300 MHz) 1.14 (t, 3H) , δ 1.37-1.72 (m, 8H) , δ 1.81-1.98 (m, 4H) , δ 2.22 {t, 2H) , δ 2.47 (t, 2H) , 6 2.47-2.55 (m, 4H) , δ 3.12-3.30 (m, 5H) , δ 3.61 (q, 2H) , δ 3.66 (s, 2H) , δ 3.86 (s, 3H) , δ 5.25 (s, 1H), δ 5.29 (s, 1H), δ 5.50 (t, 1H), δ 6.64 (t, 2H) , δ 6.85-6.89 (m, 2H) , δ 6.97 (t, 1H), δ 7.40 {d, 1H) . <1> H-NMR (CDC13, 300 MHz) 1.14 (t, 3H), δ 1.37-1.72 (m, 8H), δ 1.81-1.98 (m, 4H), δ 2.22 {t, 2H), δ 2.47 ( t, 2H), 6 2.47-2.55 (m, 4H), δ 3.12-3.30 (m, 5H), δ 3.61 (q, 2H), δ 3.66 (s, 2H), δ 3.86 (s, 3H), δ 5.25 (s, 1H), δ 5.29 (s, 1H), δ 5.50 (t, 1H), δ 6.64 (t, 2H), δ 6.85-6.89 (m, 2H), δ 6.97 (t, 1H), δ 7.40 {d, 1H).
Esempio 22 Example 22
5-[1,2]acido-ditio-3-pentanoico[6-(4-{6-[etil-(2-metossi-benzil)-animino]-amminoesano }-3,6-diossicicloesano-1,4-dienilammino)-propil]-amide (4) 5- [1,2] -dithio-3-pentanoic acid [6- (4- {6- [ethyl- (2-methoxy-benzyl) -animino] -aminohexane} -3,6-dioxycyclohexane-1,4- dienylamino) -propyl] -amide (4)
Il composto 4 è stato ottenuto dalla reazione tra LA (0.016 g 0.077 mmol) e 22 (0.035 g 0.072 mmol), aggiungendo trietilammina (30μl) , idrossibenzotriazolo (0.015 g 0.12 mmol), EDC1 (0.04g 0.21 mmol) e di nuovo trietilammina (30 μl) seguendo la procedura descritta per 1 per dare 0.040g di 4 con una resa del 83%. Compound 4 was obtained from the reaction between LA (0.016 g 0.077 mmol) and 22 (0.035 g 0.072 mmol), adding triethylamine (30μl), hydroxybenzotriazole (0.015 g 0.12 mmol), EDC1 (0.04g 0.21 mmol) and again triethylamine (30 μl) following the procedure described for 1 to give 0.040g of 4 with a yield of 83%.
ESI-MS:m/z: 673 [M+H<+>] ESI-MS: m / z: 673 [M + H <+>]
<1>H-NMR (CDC13, 300 MHz) 1.10 (t, 3H) , δ 1.37-1.72 (m, 22H) , δ 1.88-2.01 (m, 4H) , δ 2.23 (t, 2H) , δ 2.47-2.55 (m, 4H) , δ 3.18-3.62 (m, 6H) , δ 3.61 (m, 3H) , δ 3.86 (S, 3H) , δ 5.33 (s, 2H) , δ 5.48 (t, 1H), δ 6.65 (m, 2H) , δ 6.85-6.98 (m, 2H) , δ 7.29 (t, 1H), δ 7.40 (d, 1H) . <1> H-NMR (CDC13, 300 MHz) 1.10 (t, 3H), δ 1.37-1.72 (m, 22H), δ 1.88-2.01 (m, 4H), δ 2.23 (t, 2H), δ 2.47- 2.55 (m, 4H), δ 3.18-3.62 (m, 6H), δ 3.61 (m, 3H), δ 3.86 (S, 3H), δ 5.33 (s, 2H), δ 5.48 (t, 1H), δ 6.65 (m, 2H), δ 6.85-6.98 (m, 2H), δ 7.29 (t, 1H), δ 7.40 (d, 1H).
Esempio 23 Example 23
[6- (4-idrossi-3-metossi-benzilammino) -esil] -acido carbamico benzil estere (23) [6- (4-hydroxy-3-methoxy-benzylamino) -hexyl] -carbamic acid benzyl ester (23)
Ad una soluzione di N-Z-l,6-diamminoesano (0.50 g, 1.99 mmol) in trimetilortoformiato (20 mi), si è aggiunta vanillina (0.30 g, 1.99 mmol). Si è lascito in agitazione a t.a. per 1h quindi sono stati aggiunti acido acetico (0.6 ml) e NaCNBH3(0.13 g, 1.99 mmol). Si è lasciato in agitazione per una notte a t.a., quindi sono stati eliminati i solventi sotto vuoto e si è purificato il grezzo ottenuto per cromatografia a caduta. Eluendo con CH2CI2/CH3OH/NH3(9.5:0.5:0.05). si sono ottenuti 0.27 g di 23 sotto forma di olio trasparente. Resa 35%.<1>H-NMR (CDC13, 200 MHz) δ 1.20-1.59 (m, 8H), δ 2.62 (t, 2H), δ 3.13 (q, 2H), δ 3.69 (s, 2H), δ 3.75 (s, 3H), δ 4.30 (br s exch, 2H), δ 5.09 (s, 2H 1H exch), δ 6.73-6.87 (m complex, 3H). Vanillin (0.30 g, 1.99 mmol) was added to a solution of N-Z-1,6-diaminohexane (0.50 g, 1.99 mmol) in trimethylorthoformate (20 ml). He left himself in agitation at t.a. acetic acid (0.6 ml) and NaCNBH3 (0.13 g, 1.99 mmol) were then added for 1h. It was left under stirring overnight at rt, then the solvents were removed under vacuum and the crude obtained was purified by drop chromatography. Eluting with CH2CI2 / CH3OH / NH3 (9.5: 0.5: 0.05). 0.27 g of 23 were obtained in the form of transparent oil. Yield 35%. <1> H-NMR (CDC13, 200 MHz) δ 1.20-1.59 (m, 8H), δ 2.62 (t, 2H), δ 3.13 (q, 2H), δ 3.69 (s, 2H), δ 3.75 (s, 3H), δ 4.30 (br s exch, 2H), δ 5.09 (s, 2H 1H exch), δ 6.73-6.87 (m complex, 3H).
Esempio 24 Example 24
4- [ (6-Ammino -esilaminino) -metil] -2-metossi-fenolo (24) 4- [(6-Amino-hexylaminino) -methyl] -2-methoxy-phenol (24)
Ad una soluzione di 23 (0.27 g, 0.70 mmol) in metanolo (70 mi), è stato aggiunto il catalizzatore Pd-C al 10% (0.027 g) e si è effettuata un'idrogenazione catalitica fino a consumo della quantità teorica di idrogeno (8 h). Si è filtrato il catalizzatore su Celite e si è eliminato il solvente sotto vuoto a dare 0.14 g di 24 sotto forma di olio giallo. Resa 79%.1H -NMR (CDC13, 200 MHz) δ 1.28-1.63 (m, 8H), δ 2.30 (br s, 3H), δ 2.60-2.74(m, 4H), δ 3.72 (s, 2H), δ 3.89 (s, 3H), δ 6.81-6.88 (m, 3H). To a solution of 23 (0.27 g, 0.70 mmol) in methanol (70 ml), the catalyst Pd-C at 10% (0.027 g) was added and a catalytic hydrogenation was carried out until the theoretical quantity of hydrogen was consumed. (8 h). The catalyst was filtered over Celite and the solvent was removed under vacuum to give 0.14 g of 24 in the form of yellow oil. Yield 79% .1H -NMR (CDC13, 200 MHz) δ 1.28-1.63 (m, 8H), δ 2.30 (br s, 3H), δ 2.60-2.74 (m, 4H), δ 3.72 (s, 2H), δ 3.89 (s, 3H), δ 6.81-6.88 (m, 3H).
Esempi 25 Examples 25
2,5-Bis-[6-(4-idrossi-3-metossi-benzilammino) -esilammino]- [1,4]benzochinone (25) 2,5-Bis- [6- (4-hydroxy-3-methoxy-benzylamino) -hexylamino] - [1,4] benzoquinone (25)
Ad una soluzione di 2,5-dimetossi-1,4-benzochinone (0.09 g, 0.55 mmol) in etanolo 60 °C (15 mi), si è aggiunto 24 (0.23 g, 1.1 mmol). Si è lasciato in agitazione a t.a. per una notte. Si è formato un precipitato che è stato prima filtrato e poi purificato per cromatografia flash eluendo con CH2C12/CH3OH/NH3(9:1:0.1), a dare 0.051 g di 25 sotto forma di cristalli rosa. Resa 18% . Pf=172 °C. EI-MS: 609 (M+H<+>).<1>H-NMR (DMSO, 300 MHz) δ 1.27-1.67 (m, 16H), δ 2.43 (t, 4H), δ 3.20-3.31 (m, 4H), δ 3.55 (s, 4H), δ 3.74 (s, 6H), δ 5.21 (s, 2H), δ 6.70-6.72 (m, 4H), δ 6.88 (s, 2H), δ 7.72 (t exch, 2H), δ 8.79 (br s exch, 2H). To a solution of 2,5-dimethoxy-1,4-benzoquinone (0.09 g, 0.55 mmol) in ethanol 60 ° C (15 ml), 24 (0.23 g, 1.1 mmol) was added. It is left in agitation at rt. For a night. A precipitate was formed which was first filtered and then purified by flash chromatography eluting with CH2C12 / CH3OH / NH3 (9: 1: 0.1), to give 0.051 g of 25 in the form of pink crystals. Yield 18%. Pf = 172 ° C. EI-MS: 609 (M + H <+>). <1> H-NMR (DMSO, 300 MHz) δ 1.27-1.67 (m, 16H), δ 2.43 (t, 4H), δ 3.20-3.31 (m , 4H), δ 3.55 (s, 4H), δ 3.74 (s, 6H), δ 5.21 (s, 2H), δ 6.70-6.72 (m, 4H), δ 6.88 (s, 2H), δ 7.72 (t exch, 2H), δ 8.79 (br s exch, 2H).
Esempio 26 Example 26
3-[(3-benzilossicarbonilammino-propilammino) -metil]-5-metossì-indol-acido carbossilico terbutilestere (26) 3 - [(3-benzyloxycarbonylamino-propylamino) -methyl] -5-methoxy-indole-carboxylic acid terbutyl ester (26)
Ad una soluzione di N-Z-l,3-diamminopropano (0.52 g, 2.5 mmol) in trimetilortoformiato (15 ml), si è aggiunto 5-metossi-1-tert-butossicarbonilindol-3-carbossaldeide [Chem. Pharm. Bull. 48 1872-1876 (2000)] (0.69 g, 2.5 mmol). Si è lasciato in agitazione a t.a. per 1h, quindi si sono aggiunti acido acetico (0.6 mi) e NaCNBH3(0.16 g, 2.5 mmol). Si è lasciato in agitazione per 10 min a t.a. quindi si è basificata la soluzione con NaOH 2N e si è estratto con CH2C12(2 x 25 ml). Gli estratti organici riuniti sono stati lavati con acqua e anidrificati . Il solvente è stato eliminato a dare 0.96 g di 26 sotto forma di olio giallo. Resa 82%. 5-methoxy-1-tert-butoxycarbonylindol-3-carboxaldehyde [Chem. Pharm. Bull. 48 1872-1876 (2000)] (0.69 g, 2.5 mmol). It is left in agitation at rt. for 1h, then acetic acid (0.6 ml) and NaCNBH3 (0.16 g, 2.5 mmol) were added. It was left under stirring for 10 min at rt. then the solution was basified with 2N NaOH and extracted with CH2C12 (2 x 25 ml). The combined organic extracts were washed with water and dried. The solvent was removed to give 0.96 g of 26 in the form of yellow oil. Yield 82%.
<1>H-NMR (CDC13, 200 MHz) δ 1.68 (s, 9H), δ 2.09-2.13 (m, 2H), δ 2.80 (q, 2H), δ 3.35 (q, 2H), e13.65 (S, 2H), δ 3.87 (s, 3H). δ 5.09 (s, 2H), δ 5.41 {br s exch, IH), δ 6.95 (dd, 1H), δ 7.11 (s,1H), δ 7.30-7.40 (m,5H), δ 7.53 (s,1H), δ 8.03 (d,1H). <1> H-NMR (CDC13, 200 MHz) δ 1.68 (s, 9H), δ 2.09-2.13 (m, 2H), δ 2.80 (q, 2H), δ 3.35 (q, 2H), e13.65 ( S, 2H), δ 3.87 (s, 3H). δ 5.09 (s, 2H), δ 5.41 {br s exch, IH), δ 6.95 (dd, 1H), δ 7.11 (s, 1H), δ 7.30-7.40 (m, 5H), δ 7.53 (s, 1H ), δ 8.03 (d, 1H).
Esempio 27 Example 27
3-{ [(3-benzilossicarbonilammino-propil)-terbutossicarbonil -ammino]-metil}-5-metossi-indol-1-acido carbossilico terbutilestere (27) 3- {[(3-benzyloxycarbonylamino-propyl) -terbutoxycarbonyl -amino] -methyl} -5-methoxy-indole-1-carboxylic acid terbutyl ester (27)
Ad una soluzione di 26 (0.96 g, 2.05 mmol) in acetonitrile (100 mi) si sono aggiunti diterbutildicarbonato (0.54 g, 2.46 mmol) e 4-dimetilamminopiridina (0.035 g, 0.29 mmol). Si è lasciato in agitazione a 40 °C per 12h. Dopo raffreddamento, si sono elimintati i solventi e il residuo rosa ottenuto è stato ripreso con CH2C12(50 mi), lavato con soluzione di KHSO41M (1 x 50 ml) e purificato per cromatografia flash. Eluendo con etere di petrolio/etile acetato (7:3) si sono ottenuti 0.9 g di 27 sotto forma di solido gommoso giallo. Resa 78%.<1>-NMR (CDC13, 300 MHz) δ 1.54 (s, 9H), δ 1.591.68 (m, 11H), δ 3.06-3.29 (m, 4H) , δ 3.86 (s, 3H) , δ 4.53 (S, 2H) , δ 5.11 (s, 2H) , δ 6.95 (dd, IH), δ 7.28-7.36 (m, 6H) , δ 7.47 (S,1H) , δ 8.01 (d,1H) . To a solution of 26 (0.96 g, 2.05 mmol) in acetonitrile (100 ml), diterbutyldicarbonate (0.54 g, 2.46 mmol) and 4-dimethylaminopyridine (0.035 g, 0.29 mmol) were added. It was left under stirring at 40 ° C for 12h. After cooling, the solvents were eliminated and the pink residue obtained was taken up with CH2C12 (50 ml), washed with KHSO41M solution (1 x 50 ml) and purified by flash chromatography. Eluting with petroleum ether / ethyl acetate (7: 3) gave 0.9 g of 27 in the form of a yellow rubbery solid. Yield 78%. <1> -NMR (CDC13, 300 MHz) δ 1.54 (s, 9H), δ 1.591.68 (m, 11H), δ 3.06-3.29 (m, 4H), δ 3.86 (s, 3H) , δ 4.53 (S, 2H), δ 5.11 (s, 2H), δ 6.95 (dd, IH), δ 7.28-7.36 (m, 6H), δ 7.47 (S, 1H), δ 8.01 (d, 1H) .
Esempio 28 Example 28
3- { [ (3 - animino -propil) -terbutossicarbonil- animino] -metil}-5-metossi-indol-1-acido carbossilico terbutilestere (28) 3- {[(3 - amino -propyl) -terbutoxycarbonyl-amino] -methyl} -5-methoxy-indole-1-carboxylic acid terbutyl ester (28)
Ad una soluzione di 27 (0.9 g, 1.58 mmol) in metanolo (100 mi), si è aggiunto il catalizzatore Pd-C al 10% (0.09 g) e si è effettuata un'idrogenazione catalitica fino a consumo della quantità teorica di idrogeno. Si è filtrato il catalizzatore su Celite e si è eliminato il solvente sotto vuoto a dare 0.46 g di 28 sotto forma di olio trasparente. Resa 68%.<1>Ή-NMR (CDC13, 200 MHz) δ 1.54(s, 9H), δ 1.65-1.78 (m, U H), δ 2.71 (t, 2H), δ 3.24 (br s, 2H), δ 3.86 (s, 3H), δ 4.55 (s, 2H), δ 6.94 (dd, 1H), δ 7.48 (S,1H), δ 7.20-7.28 (m,1H). δ 8.00 (d,1H). To a solution of 27 (0.9 g, 1.58 mmol) in methanol (100 ml), the catalyst Pd-C at 10% (0.09 g) was added and a catalytic hydrogenation was carried out until the theoretical quantity of hydrogen was consumed. . The catalyst was filtered over Celite and the solvent was removed under vacuum to give 0.46 g of 28 in the form of transparent oil. Yield 68%. <1> Ή-NMR (CDC13, 200 MHz) δ 1.54 (s, 9H), δ 1.65-1.78 (m, U H), δ 2.71 (t, 2H), δ 3.24 (br s, 2H) , δ 3.86 (s, 3H), δ 4.55 (s, 2H), δ 6.94 (dd, 1H), δ 7.48 (S, 1H), δ 7.20-7.28 (m, 1H). δ 8.00 (d, 1H).
Esempio 29 Example 29
2,5-Bis-{3-[ (5 -metossi-N-BOC-indol-3-ilmetil) -terbutossicarbonil -animino] -propilammino } - [1,4] benzochinone (29) 2,5-Bis- {3- [(5 -methoxy-N-BOC-indol-3-ylmethyl) -terbutoxycarbonyl -animino] -propylamino} - [1,4] benzoquinone (29)
Ad una soluzione di 28 {0.059 g, 0.13 mmol) in etanolo (7 mi), si è aggiunto 2,5-dimetossi-l,4-benzochinone (0.011g, 0.065 mmol). Si è lasciato in agitazione prima a 50 °C e poi a t.a. per una notte. Si è formata una soluzione rossa, che viene concentrata sotto vuoto e purificata per cromatografia flash. Eluendo con etere di petrolio/etile acetato/CH3OH/NH3(7.5:2:0.5:0.05) si sono ottenuti 0.030 g di 29 sotto forma di olio rosso. Resa 48 %. ES-MS:994 (M+Na<+>).<1>H-NMR (CDC13, 200 MHz) δ 1.35-196 (m complex, 40H), δ 3.08-3.11 (m, 4H), δ 3.26 (m, 4H), δ 3.84 (s, 6H), δ 4.54 (s, 4H), δ 5.21 (s, 2H), δ 6.93 (dd,2H), δ 7.23 (s, 2H), δ 7.46 (s, 2H), δ 7.98 (d, 2H). To a solution of 28 {0.059 g, 0.13 mmol) in ethanol (7 ml), 2,5-dimethoxy-1,4-benzoquinone (0.011 g, 0.065 mmol) was added. It was left under stirring first at 50 ° C and then at rt. For a night. A red solution has formed, which is concentrated in vacuo and purified by flash chromatography. Eluting with petroleum ether / ethyl acetate / CH3OH / NH3 (7.5: 2: 0.5: 0.05) gave 0.030 g of 29 in the form of red oil. Yield 48%. ES-MS: 994 (M + Na <+>). <1> H-NMR (CDC13, 200 MHz) δ 1.35-196 (m complex, 40H), δ 3.08-3.11 (m, 4H), δ 3.26 ( m, 4H), δ 3.84 (s, 6H), δ 4.54 (s, 4H), δ 5.21 (s, 2H), δ 6.93 (dd, 2H), δ 7.23 (s, 2H), δ 7.46 (s, 2H), δ 7.98 (d, 2H).
Esempio 30 Example 30
2, 5-Bis-{3- [ (5-metossi-1H-indol-3-ilmetil ) -ammino] -propilammino } - [1, 4] benzochinone (30) 2,5-Bis- {3- [(5-methoxy-1H-indol-3-ylmethyl) -amino] -propylamino} - [1, 4] benzoquinone (30)
Ad. una soluzione di 29 (0.03 g, 0.031 mmol) in CH2C12(3 ml) si è aggiunto acido trifluoroacetico (0.5 ml). Si è lasciato in agitazione a t.a. per 1h quindi per aggiunta di etere si è avuta la formazione di un precipitato, che è stato raccolto per filtrazione per dare 0.02 g di 30 sotto forma di solido marrone. Resa 95%. Pf=181°C. ES-MS:595 (M+Na<+>).<1>H-NMR (CD3OD, 200 MHz) δ 2.01-2.04 (m, 4H), δ 3.14 (t, 4H), δ 3.83 (s, 6H), δ 4.42 (s, 4H), 5 5.35 (s, 2H), δ 6.89 (d, 2H), δ 7.21 (s, 2H), δ 7.32 (d,2H), δ 7.44 (S,2H). To. a solution of 29 (0.03 g, 0.031 mmol) in CH2C12 (3 ml) was added trifluoroacetic acid (0.5 ml). It is left in agitation at rt. for 1 hour a precipitate was formed by addition of ether, which was collected by filtration to give 0.02 g of 30 in the form of a brown solid. 95% yield. Pf = 181 ° C. ES-MS: 595 (M + Na <+>). <1> H-NMR (CD3OD, 200 MHz) δ 2.01-2.04 (m, 4H), δ 3.14 (t, 4H), δ 3.83 (s, 6H ), δ 4.42 (s, 4H), 5 5.35 (s, 2H), δ 6.89 (d, 2H), δ 7.21 (s, 2H), δ 7.32 (d, 2H), δ 7.44 (S, 2H).
Esempio 31 Example 31
{6-[(6-Idrossi-5,7,8-trimetil-croman-2-ilmetil) -amino]-esil}-acido carbammico benzil estere (31) {6 - [(6-Hydroxy-5,7,8-trimethyl-chroman-2-ylmethyl) -amino] -hexyl} -carbamic acid benzyl ester (31)
il composto 31 è stato ottenuto da Trolox-aldeide [Bioorg. Med. Chem. Lett. 15 3012-3015 (2005)] ed N-Z-l,6-diamminoesano seguendo la procedura descritta per 23. Resa 35%. compound 31 was obtained from Trolox-aldehyde [Bioorg. Med. Chem. Lett. 15 3012-3015 (2005)] and N-Z-1,6-diaminohexane following the procedure described for 23. Yield 35%.
Esempio 32 Example 32
2-[(6-Ammino-esillammino)-methyl]-5,7,8-trimetricroman-6-olo (32) 2 - [(6-Amino-hexylamino) -methyl] -5,7,8-trimetricroman-6-ol (32)
il composto 32 è stato ottenuto per idrogenazione catalitica di 31 seguendo la procedura descritta per 24. compound 32 was obtained by catalytic hydrogenation of 31 following the procedure described for 24.
Esempio 33 Example 33
2,5-Bis-{6- [(6-hydroxy-2,5,7,8-tetramethyl-chroman-2-ylmethyl)-amino] -hexylamino}- [1,4]benzoquinone 2,5-Bis- {6- [(6-hydroxy-2,5,7,8-tetramethyl-chroman-2-ylmethyl) -amino] -hexylamino} - [1,4] benzoquinone
(33) (33)
Il composto 33 è stato ottenuto da 32 e 2,5-dimetossi-l,4-benzochinone seguendo la procedura descritta per 25. ESI-MS: 773 (M+H<+>). Compound 33 was obtained from 32 and 2,5-dimethoxy-1,4-benzoquinone following the procedure described for 25. ESI-MS: 773 (M + H <+>).
Esempio 34 Example 34
(R)-(3-ter-Butossicarbonilamino-propil) -{3-[2-(2-fluoro-bifenil-4) -propionilamìno]-propil} -acido carbammico ter-butilestere (34) (R) - (3-tert-Butoxycarbonylamino-propyl) - {3- [2- (2-fluoro-biphenyl-4) -propionylamino] -propyl} -carbamic acid tert-butyl ester (34)
Ad una soluzione di (3-amino-propil)-(3-terbutossicarbonilamino -propil)-acido carbammico terbutilestere [European Journal of Medicinal Chemistry, 38 (2003), 117-122] (0.41 g, 1.23 mmol) in THF anidro (15 mi), si aggiunge trietilammina (0.124 g, 1.23 mmol) e mantenendo la reazione in agitazione a 0°C sotto atmosfera inerte si aggiungono l'acido (R)-(-)-2-fluoro-a-metil-4-bifenilacetico (R)-flurbiprofene (0.3 g,1.23 mmol) To a solution of (3-amino-propyl) - (3-terbutoxycarbonylamino-propyl) -carbamic acid terbutylester [European Journal of Medicinal Chemistry, 38 (2003), 117-122] (0.41 g, 1.23 mmol) in anhydrous THF ( 15 ml), triethylamine (0.124 g, 1.23 mmol) is added and the (R) - (-) - 2-fluoro-a-methyl-4- acid is added while stirring the reaction at 0 ° C under an inert atmosphere. biphenylacetic (R) -flurbiprofen (0.3 g, 1.23 mmol)
e EDCI (0.24 g, 1.23 mmol). Si lascia in agitazione, per 20 minuti a 0 °C e per un' intera giornata a temperatura ambiente. Si elimina il solvente e il residuo viene purificato con cromatografia flash. Eluendo con CH2CI2/CH3OH (9:1) si ottengono 0.36 g di 34 sotto forma di olio trasparente. Resa 52 %.<1>H-NMR (CDC13, 200 MHz) δ 1.45 (s, 18H), δ 1.56 (d, 3H), δ 1.63-1.66 (m, 4H), δ 3.08-3.19 (m, 8H), δ 3.61 (q, 1H), δ 7.16-7.22 (m, 2H), δ 7.37-7.56 (m complex, 6H). and EDCI (0.24 g, 1.23 mmol). It is left under stirring for 20 minutes at 0 ° C and for a whole day at room temperature. The solvent is removed and the residue is purified by flash chromatography. Eluting with CH2CI2 / CH3OH (9: 1) 0.36 g of 34 are obtained in the form of transparent oil. Yield 52%. <1> H-NMR (CDC13, 200 MHz) δ 1.45 (s, 18H), δ 1.56 (d, 3H), δ 1.63-1.66 (m, 4H), δ 3.08-3.19 (m, 8H ), δ 3.61 (q, 1H), δ 7.16-7.22 (m, 2H), δ 7.37-7.56 (m complex, 6H).
Esempio 35 Example 35
(R)-N-[3-(3-Amino-propilamino) -propil]-2-(2-fluorobìfenill-4) -propionamide (35) (R) -N- [3- (3-Amino-propylamino) -propyl] -2- (2-fluorobìphenyl-4) -propionamide (35)
Ad una soluzione di 34 (0.36 g, 0.64 mmol) in cloruro di metilene (15 mi) mantenuta a 0°C si aggiunge lentamente acido trifluoroacetico (0.36 g, 3,2 mmol). Si lascia in agitazione a temperatura ambiente per 24 ore. Si elimina il solvente e il residuo viene purificato con cromatografia flash. Eluendo con fase in gradiente costituita da cloruro di CH2CI2/CH3OH/NH3(7:3:0.3) e poi CH2CI2/CH3OH/NH3(5:5:0.5) si ottengono 0.13 g di 35 sotto forma di olio trasparente. Resa: 56%. 1H -NMR (CDC13, 200 MHz) δ 1.50(d, 3H), δ 1.57-1.66 (m, 4H), δ 2.58-2.78 (m, 8H), δ 3.29 (q, IH), δ 7.12-7.52 (m complex, 8H). Esempio 36 Trifluoroacetic acid (0.36 g, 3.2 mmol) is slowly added to a solution of 34 (0.36 g, 0.64 mmol) in methylene chloride (15 ml) kept at 0 ° C. It is left under stirring at room temperature for 24 hours. The solvent is removed and the residue is purified by flash chromatography. By eluting with a gradient phase consisting of chloride of CH2CI2 / CH3OH / NH3 (7: 3: 0.3) and then CH2CI2 / CH3OH / NH3 (5: 5: 0.5) 0.13 g of 35 are obtained in the form of transparent oil. Yield: 56%. 1H -NMR (CDC13, 200 MHz) δ 1.50 (d, 3H), δ 1.57-1.66 (m, 4H), δ 2.58-2.78 (m, 8H), δ 3.29 (q, IH), δ 7.12-7.52 ( m complex, 8H). Example 36
(R)-2- (2-Fluoro-bifenili-4) -N-(3-{3-[4-(3-{3-[2-(2 fluoro-bifenil-4) -propionilamino]-propilamino }-propilamino) -3,6-diosso-cicloesan-1,4-dienilamino] -propilamino }-propil)-propionamide (36) (R) -2- (2-Fluoro-biphenyl-4) -N- (3- {3- [4- (3- {3- [2- (2 fluoro-biphenyl-4) -propionylamino] -propylamino} -propylamino) -3,6-dioxo-cyclohexane-1,4-dienylamino] -propylamino} -propyl) -propionamide (36)
Ad una soluzione di 35 (0.13 g, 0.36 mmol) in etanolo (10 mi), si aggiunge 2 ,5-dimetossi-1,4-benzochinone (0.030 g, 0.18 mmol). Si lascia in agitazione prima a 50 °C per 3h e poi a t.a. per una notte. Si forma un precipitato arancione che viene filtrato a dare 0.055 g di 36. Resa 37%. Pf: 136 °C. ES-MS: 819.<1>H-NMR (CDCl3, 200 MHz) δ 1.55 (d, 6H), δ 1.66-1.81 (m, 8H), δ 2.58-2.74 (m, 8H), δ 3.20 (q, 4H), δ 3.34-3.47 (m, 4H), δ 3.58 (q,2H), δ 5.29 (s, 2H), δ 6.98 (br t exch, 1H), δ 7.13-7.56 (m complex, 16H), δ 8.46 (br exch, 2H). To a solution of 35 (0.13 g, 0.36 mmol) in ethanol (10 ml), 2,5-dimethoxy-1,4-benzoquinone (0.030 g, 0.18 mmol) is added. It is left under stirring first at 50 ° C for 3h and then at rt. For a night. An orange precipitate is formed which is filtered to give 0.055 g of 36. Yield 37%. Pf: 136 ° C. ES-MS: 819. <1> H-NMR (CDCl3, 200 MHz) δ 1.55 (d, 6H), δ 1.66-1.81 (m, 8H), δ 2.58-2.74 (m, 8H), δ 3.20 (q , 4H), δ 3.34-3.47 (m, 4H), δ 3.58 (q, 2H), δ 5.29 (s, 2H), δ 6.98 (br t exch, 1H), δ 7.13-7.56 (m complex, 16H) , δ 8.46 (br exch, 2H).
Esempio 37 Example 37
{3-[2-(2-fluoro-bifenil-4-il) -propionilammino] -propil}-acido carbammico benzil estere (37) {3- [2- (2-fluoro-biphenyl-4-yl) -propionylamino] -propyl} -carbamic acid benzyl ester (37)
Ad una soluzione di (±)-flurbiprofene (0.87 g, 3.56 mmol) in cloroformio (15 mi), si aggiunge cloruro di tionile (1.27 g, 10.7 mmol) e si lascia in agitazione, per 2h a 60 °C. Per eliminazione dei solventi si ottiene un residuo che è sciolto in cloroformio (20 mi) e trattato con trietilammina To a solution of (±) -flurbiprofen (0.87 g, 3.56 mmol) in chloroform (15 ml), thionyl chloride (1.27 g, 10.7 mmol) is added and the mixture is left under stirring for 2h at 60 ° C. By eliminating the solvents, a residue is obtained which is dissolved in chloroform (20 ml) and treated with triethylamine
(0.5 mi, 3.56 mmol ) e 6 (0.74 g, 3.56 mmol ). Si lascia in agitazione a t.a. per una notte e si lava la miscela di reazione con acqua (30 mi), K2C0320% (30 ml) ed HC1 1 N (30 ml). Si anidrificano gli estratti organici, si eliminano i solventi e il residuo viene purificato con cromatografia flash. Eluendo con etile acetato/etere di petrolio (7:3) si ottengono 0.21 g di 37 sotto forma di solido bianco. Resa 14%.<1>H-NMR (CDC13, 200 MHz) δ 1.57-1.65 (m, 5H), δ 3.20 (q , 2H), δ 3.31 (q, 2H), δ 3.60 (q, 1H), δ 5.11 (s, 2H), δ 5.23 (br S exch, IH), δ 6.12 (br s exch, 1H), δ 7.13-7.59 (m,13H). Esempio 38 (0.5 ml, 3.56 mmol) and 6 (0.74 g, 3.56 mmol). It is left under agitation at rt. overnight and the reaction mixture is washed with water (30 ml), K2CO320% (30 ml) and 1 N HCl (30 ml). The organic extracts are dried, the solvents are removed and the residue is purified with flash chromatography. By eluting with ethyl acetate / petroleum ether (7: 3) 0.21 g of 37 are obtained in the form of a white solid. Yield 14%. <1> H-NMR (CDC13, 200 MHz) δ 1.57-1.65 (m, 5H), δ 3.20 (q, 2H), δ 3.31 (q, 2H), δ 3.60 (q, 1H), δ 5.11 (s, 2H), δ 5.23 (br S exch, IH), δ 6.12 (br s exch, 1H), δ 7.13-7.59 (m, 13H). Example 38
N-(3-ammino-propi l)-2-(2-fluoro-bifenil-4-il) -propionammide (38) N- (3-amino-propyl) -2- (2-fluoro-biphenyl-4-yl) -propionamide (38)
Ad una soluzione di 37 (0.21 g, 0.48 mmol) in metanolo (60 mi), si aggiunge il catalizzatore Pd-C al 10% (0.021g) e si effettua un'idrogenazione catalitica fino a consumo della quantità teorica di idrogeno. Si filtra il catalizzatore su Celite e si elimina il solvente sotto vuoto a dare 0.13 g di 38 sotto forma di olio giallo. Resa 93%.<1>H-NMR (CDC13, 200 MHz) δ 1.58-1.63 (m, 5H 2H exch), δ 2.78 (q, 2H), δ 3.38 (t, 2H), δ 3.49-3.63 (m, 1H), δ 6.54 (br s exch, 1H), δ 7.15-7.61 (m complex, 9H). To a solution of 37 (0.21 g, 0.48 mmol) in methanol (60 ml), the catalyst Pd-C at 10% (0.021g) is added and a catalytic hydrogenation is carried out until the theoretical quantity of hydrogen is consumed. The catalyst is filtered on Celite and the solvent is removed under vacuum to give 0.13 g of 38 in the form of yellow oil. Yield 93%. <1> H-NMR (CDC13, 200 MHz) δ 1.58-1.63 (m, 5H 2H exch), δ 2.78 (q, 2H), δ 3.38 (t, 2H), δ 3.49-3.63 (m , 1H), δ 6.54 (br s exch, 1H), δ 7.15-7.61 (m complex, 9H).
Esempio 39 Example 39
2- (2-fluoro-bifenil-4-il)-N- [3-(4-{3-[2-(2-fluorobifenil-4-il) -propionilammino] -propilammino }-3,6-diosso-cicloesano-1,4-dienilammino) -propil]-propionammide (39) 2- (2-fluoro-biphenyl-4-yl) -N- [3- (4- {3- [2- (2-fluorobiphenyl-4-yl) -propionylamino] -propylamino} -3,6-dioxo- cyclohexane-1,4-dienylamino) -propyl] -propionamide (39)
Ad una soluzione di 38 (0.13 g, 0.43 mmol) in etanolo (7 mi), si aggiunge 2,5-dimetossi-1,4-benzochinone (0.037 g, 0.22 mmol). Si lascia in agitazione prima a 50 °C per 3h e poi a t.a. per una notte. Si forma un precipitato arancione che viene prima filtrato e poi cristallizzato da etanolo/cloroformio a dare 0.043 g di 39 sotto forma di cristalli rossi. Resa 29%. Pf=178°C. ES-MS: 727 (M+Na<+>). 1H-NMR (CDCI3, 300 MHz) δ 1.58-1.60 (s, 10H), δ 1.81-1.85 (m, 4H), δ 3.16 (q, 4H), δ 3.23-3.38 (m, 4H), δ 3.62 (q, 2H), δ 5.28 (s,2H), δ 5.57 (br t exch, 2H), δ 6.76 (br t exch, 2H), δ 7.19 (t, 4H), δ 7.29-7.60 (m complex, 12H). To a solution of 38 (0.13 g, 0.43 mmol) in ethanol (7 ml), 2,5-dimethoxy-1,4-benzoquinone (0.037 g, 0.22 mmol) is added. It is left under stirring first at 50 ° C for 3h and then at rt. For a night. An orange precipitate is formed which is first filtered and then crystallized from ethanol / chloroform to give 0.043 g of 39 in the form of red crystals. Yield 29%. Pf = 178 ° C. ES-MS: 727 (M + Na <+>). 1H-NMR (CDCI3, 300 MHz) δ 1.58-1.60 (s, 10H), δ 1.81-1.85 (m, 4H), δ 3.16 (q, 4H), δ 3.23-3.38 (m, 4H), δ 3.62 ( q, 2H), δ 5.28 (s, 2H), δ 5.57 (br t exch, 2H), δ 6.76 (br t exch, 2H), δ 7.19 (t, 4H), δ 7.29-7.60 (m complex, 12H ).
Determinazione potenza inibitoria su HuAChE e BChE Determination of inhibitory potency on HuAChE and BChE
L'attività dei composti in esame, espressa come IC50, è stata valutata secondo il metodo spettrofotometrico di Ellman [Ellman G.L., Courtney K.D., Andrei V. , Featherstone R.M. Biochem. Pharmacol. 1961, 7, 88-95] su acetilcolinesterasi ricombinante umana (E.C. 3.1.1.7) (AChE o HuAChE) e butirrilcolinesterasi (E.C. 3.1.1.8) (BChE) da siero umano. I valori di IC50rappresentano le concentrazioni di inibitore necessarie per ridurre l'attività enzimatica del 50% e sono la media di due misure indipendenti, ognuna in duplicato. The activity of the compounds under examination, expressed as IC50, was evaluated according to the Ellman spectrophotometric method [Ellman G.L., Courtney K.D., Andrei V., Featherstone R.M. Biochem. Pharmacol. 1961, 7, 88-95] on recombinant human acetylcholinesterase (E.C. 3.1.1.7) (AChE or HuAChE) and butyrylcholinesterase (E.C. 3.1.1.8) (BChE) from human serum. The IC50 values represent the inhibitor concentrations needed to reduce enzyme activity by 50% and are the average of two independent measurements, each in duplicate.
I composti sintetizzati (1, 2, 3, 4, 25, 30, 33, 36 e 39, in particolare 36 e 39) presentano degli interessanti valori di IC50AChE e IC50BChE, almeno paragonabili a quelli del farmaco anti-AD tacrina. The synthesized compounds (1, 2, 3, 4, 25, 30, 33, 36 and 39, in particular 36 and 39) show interesting values of IC50AChE and IC50BChE, at least comparable to those of the anti-AD drug tacrine.
Esempio 33 Example 33
Inibizione aggregazione β-amiloide (1-40) indotta da AChE ricombinante umana Inhibition of human recombinant AChE-induced β-amyloid (1-40) aggregation
L'attività inibitoria sull'aggregazione del peptide β-amiloide(1-40) indotta da AChE ricombinante umana viene determinata mediante un metodo fiorimetrico basato sull'uso della Tioflavina τ (Bartolini, M.; Bertucci, C.; Cavrini, V.; Andrisano, V. β-Amyloid aggregation induced by human acetylcholinesterase : inhibition studies. Biochem. Pharmacol. 2003, 65, 407-416). I composti vengono testati ad una concentrazione fissa pari a 100 μΜ. I composti sintetizzati (1, 2, 2, 4, 25, 30, 33, 36 e 39, in particolare 36 e 39) presentano interessanti valori della % di inibizione dell'aggregazione di Αβ40 indotta da AChE. The inhibitory activity on the aggregation of the β-amyloid peptide (1-40) induced by human recombinant AChE is determined by a fiorimetric method based on the use of Thioflavin τ (Bartolini, M .; Bertucci, C .; Cavrini, V. ; Andrisano, V. β-Amyloid aggregation induced by human acetylcholinesterase: inhibition studies. Biochem. Pharmacol. 2003, 65, 407-416). Compounds are tested at a fixed concentration of 100 μΜ. The synthesized compounds (1, 2, 2, 4, 25, 30, 33, 36 and 39, in particular 36 and 39) show interesting values of the% inhibition of the aggregation of Αβ40 induced by AChE.
Esempio 34 Example 34
L'attività antiossidante intracellulare dei composti sintetizzati viene testata misurando la formazione di specie intracellulari reattive all'ossigeno (ROS) determinate dall'esposizione delle cellule SH-SY5Y (le culture cellulari sono state trattate come descritto nell'esempio 26) al ter-butil idroperossido (t-BuOOH), un composto utilizzato per indurre un danno ossidativo. La formazione di ROS intracellulare viene determinata utilizzando una sonda fluorescente, DCFH-DA, come descritto da Wang H. et al. (H. Wang, J. A. Joseph, Free Radic. Biol. Med. 1999, 27, 612). The intracellular antioxidant activity of the synthesized compounds is tested by measuring the formation of oxygen reactive intracellular species (ROS) determined by the exposure of SH-SY5Y cells (cell cultures were treated as described in Example 26) to tert-butyl hydroperoxide (t-BuOOH), a compound used to induce oxidative damage. The formation of intracellular ROS is determined using a fluorescent probe, DCFH-DA, as described by Wang H. et al. (H. Wang, J. A. Joseph, Free Radic. Biol. Med. 1999, 27, 612).
I composti sintetizzati (1, 2, 3, 4, 25, 30, 33, 36 e 39), particolarmente 1, 2, 3, 4, 25, 30 e 33, presentano un interessante profilo antiossidante. The synthesized compounds (1, 2, 3, 4, 25, 30, 33, 36 and 39), particularly 1, 2, 3, 4, 25, 30 and 33, have an interesting antioxidant profile.
Esempio 35 Example 35
Gli effetti di tossicità dei composti sintetizzati (in particolare 1, 2, 3, 4, 25, 30, 33, 36 e 39) e LA vengono prima determinati con prove colorimetriche con MTT in cellule SH-SY5Y simili alle neuronali umane, come descritto da Mosmann et al. (Mosmann, T. Rapid colorimetrie assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J. Immunol. Methods 1983, 65, 55-63). The toxicity effects of the synthesized compounds (particularly 1, 2, 3, 4, 25, 30, 33, 36 and 39) and LA are first determined by colorimetric tests with MTT in human neuron-like SH-SY5Y cells, as described by Mosmann et al. (Mosmann, T. Rapid colorimetrie assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J. Immunol. Methods 1983, 65, 55-63).
Le rilevazioni vengono effettuate con uno spettrofotometro (TECAN<®>, Spectra model Classic, Salizburg, Austria) ad una lunghezza d'onda di 405 nm. La vitalità cellulare viene espressa come percentuale di cellule di controllo e viene calcolata con la formula Ft/Fntx 100, dove Ft= assorbanza di neuroni trattati e Fnt= assorbanza di neuroni non trattati. The measurements are made with a spectrophotometer (TECAN <®>, Spectra model Classic, Salizburg, Austria) at a wavelength of 405 nm. Cell viability is expressed as a percentage of control cells and is calculated with the formula Ft / Fntx 100, where Ft = absorbance of treated neurons and Fnt = absorbance of untreated neurons.
Le cellule SH-SY5Y, vengono cresciute a 37°C in un incubatore umidificato con il 5% di C02in terreno Dulbecco's modified Eagle's medium addizionato di 10% di siero fetale di vitello (FCS), glutammina 2 mM, penicillina u/mL e streptomicina 50 μg/mL. SH-SY5Y cells are grown at 37 ° C in a humidified incubator with 5% C02 in Dulbecco's modified Eagle's medium added with 10% fetal calf serum (FCS), 2 mM glutamine, u / mL penicillin and streptomycin. 50 μg / mL.
Il trattamento di cellule SH-SY5Y con i composti sintetizzati (0.1-50 μΜ) non porta a variazioni della vitalità cellulare. Viceversa, i composti sono in grado di proteggere le cellule SH-SY5Y dalla tossicità indotta da Αβ(1-42). Treatment of SH-SY5Y cells with the synthesized compounds (0.1-50 μΜ) does not lead to changes in cell viability. Conversely, the compounds are able to protect SH-SY5Y cells from Αβ-induced toxicity (1-42).
Esempio 36 Example 36
L'azione antiaggregante dei composti sintetizzati (in particolare 1, 2, 2, 4, 25, 30, 33, 36 e 39) nei confronti del peptide Αβ(1-42) viene determinata mediante un saggio fluorimetrico basato sul marker Tioflavina T. [Bartolini et al., ChemBioChem, 2007, in press]. I composti sintetizzati presentano un interessante profilo anti-amiloideo. The antiplatelet action of the synthesized compounds (in particular 1, 2, 2, 4, 25, 30, 33, 36 and 39) against the Αβ (1-42) peptide is determined by a fluorimetric assay based on the Tioflavine T marker. [Bartolini et al., ChemBioChem, 2007, in press]. The synthesized compounds exhibit an interesting anti-amyloid profile.
Esempio 37 Example 37
Viene testata la specificità per NQO1 (Sigma). I composti sintetizzati (in particolare 1, 2, 3, 4, 25, 30, 33, 36 e 39) vengono testati seguendo il variazione di assorbanza del citocromo c come accettore secondario, il Menadione viene usato come composto di riferimento. Ciascuna reazione consiste di NADH, citocromo c, NQO1 ed il composto da testare in un volume di tris-HC1 contenente albumina di siero di bovino. Le reazioni cominciano con l'addizione di NADH e la riduzione del citocromo c viene monitorata a 550-540 nm. Specificity for NQO1 (Sigma) is tested. The synthesized compounds (in particular 1, 2, 3, 4, 25, 30, 33, 36 and 39) are tested following the change in absorbance of cytochrome c as a secondary acceptor, Menadione is used as a reference compound. Each reaction consists of NADH, cytochrome c, NQO1 and the compound to be tested in a volume of tris-HCl containing bovine serum albumin. The reactions begin with the addition of NADH and the reduction of cytochrome c is monitored at 550-540 nm.
I composti sintetizzati mostrano comportamenti interessanti . The synthesized compounds exhibit interesting behaviors.
Esempio 38 Example 38
I composti sintetizzati (in particolare 1, 2, 3, 4, 25, 30, 33, 36 e 39) vengono testati in vivo secondo quanto descritto all'interno della domanda di brevetto PCT/IT03/00227 (in particolare si veda l'esempio 55), il cui viene qui richiamato integralmente per completezza di descrizione. The synthesized compounds (in particular 1, 2, 3, 4, 25, 30, 33, 36 and 39) are tested in vivo as described in the patent application PCT / IT03 / 00227 (in particular see the example 55), which is referred to here in its entirety for the sake of completeness of description.
I composti sintetizzati mostrano un'interessante attività in vivo. The synthesized compounds show interesting in vivo activity.
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