DESCRIZIONEDESCRIPTION
Annessa a domanda di brevetto per INVENZIONE INDUSTRIALE avente per titoloAttached to a patent application for an INDUSTRIAL INVENTION having as its title
?Composti triptamminici non allucinogeni, preparazione, composizioni farmaceutiche e usi relativi??Non-hallucinogenic tryptamine compounds, preparation, pharmaceutical compositions and related uses?
CAMPO DELL'INVENZIONEFIELD OF INVENTION
La presente invenzione si riferisce a composti triptamminici non allucinogeni, alla preparazione, alle composizioni farmaceutiche e agli usi relativi.The present invention relates to non-hallucinogenic tryptamine compounds, the preparation, the pharmaceutical compositions and the uses thereof.
TECNICA NOTATECHNIQUE NOTE
? noto che la psilocibina, un alcaloide triptamminico isolato da vari generi di funghi includendo il genere Psilocybe, e il suo metabolita attivo Psilocina, si legano al recettore della 5-idrossi triptammina (serotonina) 5-HT2A nel sistema nervoso centrale (Central Nervous System, CNS) determinando attivit? allucinogene, ansiolitiche e psicoattive. Bench? la psilocibina e i suoi derivati siano attualmente oggetto di indagini tra gli altri per il trattamento della depressione grave, ansia, alcolismo e dipendenza da nicotina, l?attivit? psichedelica di queste molecole rappresenta un effetto collaterale grave per lo sviluppo di nuovi agenti terapeutici. Di recente ? stato proposto che gli psichedelici possano essere utili nel trattamento di neuroinfiammazione e del dolore cronico, fornendo sollievo laddove gli analgesici convenzionali non riescono (?The psychedelic remedy for chronic pain?,Psilocybin, a tryptamine alkaloid isolated from various mushroom genera including the genus Psilocybe, and its active metabolite Psilocin are known to bind to the 5-hydroxytryptamine (serotonin) 5-HT2A receptor in the central nervous system (CNS) resulting in hallucinogenic, anxiolytic and psychoactive activities. Although psilocybin and its derivatives are currently being investigated for the treatment of major depression, anxiety, alcoholism and nicotine addiction among others, the psychedelic activity of these molecules represents a serious side effect for the development of new therapeutic agents. It has recently been proposed that psychedelics may be useful in the treatment of neuroinflammation and chronic pain, providing relief where conventional analgesics fail (?The psychedelic remedy for chronic pain?,
Nature (2022) vol. 609, S100-S102 (DOI: 10.1038/d41586-022-02878-3); ?From psychiatry to neurology: Psychedelics as prospective therapeutics for neurodegenerative disorders?,Nature (2022) vol. 609, S100-S102 (DOI: 10.1038/d41586-022-02878-3); ?From psychiatry to neurology: Psychedelics as prospective therapeutics for neurodegenerative disorders?,
Journal of Neurochemistry (2022), vol.162, p.89?108 (DOI: 10.1111/jnc.15509).Journal of Neurochemistry (2022), vol.162, p.89?108 (DOI: 10.1111/jnc.15509).
Oltre al CNS, livelli elevati di espressione del recettore della 5-HT2A in altre parti del corpo quali l?intestino, le piastrine e le cellule endoteliali suggeriscono che il recettore della 5-HT2A ricopre ruoli fondamentali in altri aspetti della fisiologia. Ci? rende i recettori della 5-HT2A periferici bersagli promettenti per lo sviluppo di nuove molecole con potenti propriet? antiinfiammatorie.In addition to the CNS, elevated levels of 5-HT2A receptor expression in other parts of the body such as the intestine, platelets, and endothelial cells suggest that the 5-HT2A receptor plays critical roles in other aspects of physiology. This makes peripheral 5-HT2A receptors promising targets for the development of novel molecules with potent anti-inflammatory properties.
Scoperte recenti hanno dimostrato che un?attivazione dei recettori della 5-HT2A ha determinato una risposta anti-infiammatoria in un modello di ratto di asma (?Structure?Activity Relationship Analysis of Psychedelics in a Rat Model of Asthma Reveals the Anti-Inflammatory Pharmacophore?,Recent findings have shown that an activation of 5-HT2A receptors resulted in an anti-inflammatory response in a rat model of asthma (Structure?Activity Relationship Analysis of Psychedelics in a Rat Model of Asthma Reveals the Anti-Inflammatory Pharmacophore?,
ACS Pharmacol. Transl. Sci. (2021), vol. 4, p. 488?502 (DOI: 10.1021/acsptsci.0c00063) e infiammazione mediata da fattore di necrosi tumorale alfa (TNF-?) (Serotonin 5-HT2A Receptor Activation Blocks TNF-? Mediated Inflammation In Vivo, Felix Nau Jr, Bangning Yu, David Martin, Charles D. Nichols, PLoS ONE (2013), vol. 8(10): e75426 https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0075426) . Inoltre, ? stato trovato che l?attivazione dei recettori della 5-HT2A riduce il dolore neuropatico in seguito a una lesione del midollo spinale (Activation of 5-HT2A Receptors Restores KCC2 Function and Reduces Neuropathic Pain after Spinal Cord Injury,ACS Pharmacol. Transl. Sci. (2021), vol. 4, p. 488?502 (DOI: 10.1021/acsptsci.0c00063) and tumor necrosis factor-alpha (TNF-?)-mediated inflammation (Serotonin 5-HT2A Receptor Activation Blocks TNF-? Mediated Inflammation In Vivo, Felix Nau Jr, Bangning Yu, David Martin, Charles D. Nichols, PLoS ONE (2013), vol. 8(10): e75426 https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0075426). Furthermore, ? Activation of 5-HT2A Receptors Restores KCC2 Function and Reduces Neuropathic Pain after Spinal Cord Injury, has been found to reduce neuropathic pain following spinal cord injury (
Neuroscience (2018), vol. 387, p. 48?57, https://www.sciencedirect.com/science/article/pii/S0306452217305997). Sono stati compiuti alcuni tentativi al fine di ridurre il tasso di trasporto di piccole molecole attraverso la BBB (WO2005058367, che descrive l?attacco covalente di un polimero idrosolubile a farmaci a base di piccole molecole; WO2003032990, che divulga coniugati polimerici di antagonisti degli oppioidi con un polimero, quale poli(etilen glicole).Neuroscience (2018), vol. 387, p. 48?57, https://www.sciencedirect.com/science/article/pii/S0306452217305997). Some attempts have been made to reduce the rate of transport of small molecules across the BBB (WO2005058367, which describes the covalent attachment of a water-soluble polymer to small molecule drugs; WO2003032990, which discloses polymeric conjugates of opioid antagonists with a polymer, such as poly(ethylene glycol).
In questo contesto, sono necessari derivati triptamminici che non sono in grado di attraversare la BBB al fine di modulare l'attivit? di recettori della 5-HT2A periferici, che rappresentano molecole ideali per lo sviluppo di farmaci anti-infiammatori non allucinogeni.In this context, tryptamine derivatives that are unable to cross the BBB are needed to modulate the activity of peripheral 5-HT2A receptors, which represent ideal molecules for the development of non-hallucinogenic anti-inflammatory drugs.
DEFINIZIONIDEFINITIONS
Se non definito altrimenti, tutti i termini dell?arte, le notazioni e altri termini scientifici usati nella presente sono intesi avere i significati comunemente compresi dai tecnici del ramo a cui appartiene questa descrizione. In alcuni casi, termini con significati comunemente compresi sono qui definiti per chiarezza e/o per rapido riferimento; di conseguenza, l?inclusione di queste definizioni in questa descrizione non deve essere interpretata come rappresentante una differenza sostanziale rispetto a ci? che ? generalmente compreso nell?arte.Unless otherwise defined, all terms of the art, notations and other scientific terms used herein are intended to have the meanings commonly understood by those skilled in the art to which this specification pertains. In some cases, terms with commonly understood meanings are defined herein for clarity and/or ready reference; accordingly, the inclusion of these definitions in this specification should not be construed as representing a material difference from what is generally understood in the art.
I termini ?comprendere?, ?avere?, ?includere?, ?contenere?, ?comprendente/i?, ?avente/i?, ?includente/i? e ?contenente/i? sono da intendersi come termini aperti (ossia, il significato ?comprendente/i, in via non limitativa?) e sono da considerarsi come supporto anche per espressioni come ?sono costituiti essenzialmente da?, ?costituiti essenzialmente da?, ?sono costituiti da? o ?costituiti da?.The terms ?comprise?, ?have?, ?include?, ?contain?, ?comprising?, ?having?, ?including? and ?containing? are to be understood as open terms (i.e., the meaning ?comprising, but not limited to?) and are to be considered as a support also for expressions such as ?are essentially constituted by?, ?essentially constituted by?, ?are constituted by? or ?constituted by?.
Per tutti gli intervalli indicati nel testo e nelle rivendicazioni della presente domanda di brevetto, resta inteso che sono inclusi gli estremi di questi intervalli.For all ranges indicated in the text and claims of this patent application, it is understood that the extremes of these ranges are included.
I precursori triptamminici usati come punti di partenza nella presente invenzione possono essere ottenuti in modo sintetico e sono analoghi alle triptammine presenti naturalmente in funghi contenenti psilocibina, preferibilmente in funghi contenenti psilocibina psichedelici appartenenti al genere Psilocybe.The tryptamine precursors used as starting points in the present invention can be obtained synthetically and are analogous to tryptamines naturally occurring in psilocybin-containing mushrooms, preferably in psychedelic psilocybin-containing mushrooms belonging to the genus Psilocybe.
I funghi contenenti psilocibina psichedelici includono un gruppo informale polifiletico di funghi che contengono psilocibina, psilocina, o entrambe all?interno della loro biomassa, tipicamente all?interno dei loro corpi fruttiferi, il che determina la loro attivazione di una reazione psichedelica in un soggetto.Psychedelic psilocybin mushrooms include an informal polyphyletic group of mushrooms that contain psilocybin, psilocin, or both within their biomass, typically within their fruiting bodies, which results in their triggering a psychedelic response in a subject.
Triptammine preferite presenti naturalmente in funghi contenenti psilocibina che possono essere usate nella presente sono triptammine non fosforilate, come psilocina, norpsilocina, 4-idrossitriptammina e/o 4-idrossi?N,N,N-trimetiltriptammina, e combinazioni relative.Preferred tryptamines naturally occurring in psilocybin-containing mushrooms that may be used herein are non-phosphorylated tryptamines, such as psilocin, norpsilocin, 4-hydroxytryptamine, and/or 4-hydroxy-N,N,N-trimethyltryptamine, and combinations thereof.
I sali, derivati, idrato o solvato farmaceuticamente accettabili delle triptammine sopra citate presenti naturalmente in funghi contenenti psilocibina sono compresi anch?essi nella definizione.Pharmaceutically acceptable salts, derivatives, hydrates or solvates of the above-mentioned tryptamines naturally occurring in psilocybin-containing mushrooms are also included in the definition.
L'espressione ?genere Psilocybe? pu? riferirsi ai seguenti esempi non limitativi di funghi adatti contenenti composti psichedelici simili a psilocibina: Psilocybe atlantis, Psilocybe azurenscens, Psilocybe bohemica, Psylocibe baeocystis, Psilocybe cyanescens, Psilocybe cubensis, Psilocybe tampanensis, Psilocybe hoogshagenii Psilocybe mexicana, Psilocybe ovoideocystidiata, Psilocybe semilanceata Psilocybe weraroa, Psilocybe stuntzii, Psilocybe cyanofibrillosa, Psilocybe zapotacorum, Psilocybe yungensis, Psilocybe liniformans, Psilocybe xalapensis, Psilocybe venenata, Psilocybe subtropicalis, Psilocybe singer, Psilocybe schultesii, Psilocybe rostrata, Psilocybe quebecensis, Psilocybe pintonii, Psilocybe puberula, Psilocybe mairei, Psilocybe laurae, Psilocybe kumaenorum, Psilocy beheimii, Psilocy begalindoi, Psilocybe fmetaria, Psilocy beegonii, Psilocybe dumontii, Psilocybe carbonaria, Psilocybe cordispora, Psilocybe bispora, Psilocybe aucklandii, e combinazioni relative.The expression ?genus Psilocybe? can? See the following non-limiting examples of suitable mushrooms containing psilocybin-like psychedelic compounds: Psilocybe atlantis, Psilocybe azurenscens, Psilocybe bohemica, Psilocybe baeocystis, Psilocybe cyanescens, Psilocybe cubensis, Psilocybe tampanensis, Psilocybe hoogshagenii Psilocybe mexicana, Psilocybe ovoideocystidiata, Psilocybe semilanceata Psilocybe weraroa, Psilocybe stuntzii, Psilocybe cyanofibrillosa, Psilocybe zapotacorum, Psilocybe yungensis, Psilocybe liniformans, Psilocybe xalapensis, Psilocybe venenata, Psilocybe subtropicalis, Psilocybe singer, Psilocybe schultesii, Psilocybe rostrata, Psilocybe quebecensis, Psilocybe pintonii, Psilocybe puberula, Psilocybe mairei, Psilocybe laurae, Psilocybe kumaenorum, Psilocy beheimii, Psilocy begalindoi, Psilocybe fmetaria, Psilocy beegonii, Psilocybe dumontii, Psilocybe carbonaria, Psilocybe cordispora, Psilocybe bispora, Psilocybe aucklandii, and related combinations.
Nella presente l?espressione ?sali o derivati farmaceuticamente accettabili? si riferisce a quei sali o derivati che possiedono l?efficacia e le propriet? biologiche del composto salificato o derivatizzato e che non producono reazioni avverse quando somministrati a un mammifero, preferibilmente un essere umano. I sali farmaceuticamente accettabili possono essere sali inorganici od organici; esempi di sali farmaceuticamente accettabili includono, in via non limitativa: carbonato, cloridrato, bromidrato, solfato, idrogenosolfato, citrato, maleato, fumarato, trifluoroacetato, 2-naftalensolfonato e para-toluensolfonato. Ulteriori informazioni su sali farmaceuticamente accettabili possono essere trovate in Handbook of pharmaceutical salts, 127-133, (2008), incorporato nella presente per riferimento. I derivati farmaceuticamente accettabili includono gli esteri, gli eteri e gli N-ossidi.In this publication, the term ?pharmaceutically acceptable salts or derivatives? refers to those salts or derivatives that possess the efficacy and biological properties of the salted or derivatized compound and that do not produce adverse reactions when administered to a mammal, preferably a human. Pharmaceutically acceptable salts may be inorganic or organic salts; examples of pharmaceutically acceptable salts include, but are not limited to: carbonate, hydrochloride, hydrobromide, sulfate, hydrogen sulfate, citrate, maleate, fumarate, trifluoroacetate, 2-naphthalene sulfonate, and para-toluene sulfonate. Further information on pharmaceutically acceptable salts can be found in Handbook of pharmaceutical salts, 127-133, (2008), incorporated herein by reference. Pharmaceutically acceptable derivatives include esters, ethers, and N-oxides.
?Psilocibina? ? il nome comune di 4-fosforilossi-N,N-dimetiltriptammina. ?Psilocina? ? il nome comune di 4-idrossi-N,N-dimetiltriptammina.?Psilocybin? is the common name for 4-phosphoryloxy-N,N-dimethyltryptamine. ?Psilocin? is the common name for 4-hydroxy-N,N-dimethyltryptamine.
?Norpsilocina? ? il nome comune di 4-idrossi-N-metiltriptammina.?Norpsilocin? is the common name for 4-hydroxy-N-methyltryptamine.
Il termine ?MAOI? indica inibitori delle monoammino ossidasi. I MAOI usati nella presente invenzione appartengono alla classe ?-carbolinica di inibitori e sono selezionati tra norarmano, perlolirina, armolo, cordisinine tetraidroarmina, 6-metossiarmalano, armalano, armalina, armalolo, diidro?-carboline (DH?C), tetraidro-?-carbolina (TH?C), metil-tetraidro-?carbolina MTH?C, pinolina, 1-triclorometil-1,2,3,4-tetraidro-b-carbolina (TaClo), 6-metossitetraidroarmalano, etil ?-carbolin-3-carbossilato (?CCE), ?-carbolin-3-carbossilato (?CCM), manzamina A, manzamina X, 6-deossimanzamina X, manzamina Y, 8-idrossimanzamina A, 8-metossimanzamina A, 6-idrossimanzamina A, 3,4-diidromanzamina A, ent-8-idrossimanzamina A, ent-manzamina F, neo-kauluamina, xestomanzamina B, irtioerectine A, gesashidina A, plakortamine A, plakortamine B, lucartamidi D, plakortamine C, eudistomidine, trectandramina, fascaplisina e/o sali, derivati, idrato o solvato e/o combinazioni relative.The term “MAOI” indicates monoamine oxidase inhibitors. The MAOIs used in the present invention belong to the ?-carboline class of inhibitors and are selected from norharman, perlolyrin, harmol, cordisinin tetrahydroharmine, 6-methoxyharmalan, harmalane, harmaline, harmalol, dihydro?-carbolines (DH?C), tetrahydro-?-carboline (TH?C), methyl-tetrahydro-?-carboline MTH?C, pinoline, 1-trichloromethyl-1,2,3,4-tetrahydro-b-carboline (TaClo), 6-methoxytetrahydroharmalan, ethyl ?-carboline-3-carboxylate (?CCE), ?-carboline-3-carboxylate (?CCM), manzamine A, manzamine X, 6-deoxymizantamine X, manzamine Y, 8-hydroxymanzamine A, 8-methoxymizantamine A, 6-hydroxymanzamine A, 3,4-dihydromanzamine A, ent-8-hydroxymanzamine A, ent-manzamine F, neo-kauluamine, xestomanzamine B, irtioerectine A, gesashidin A, plakortamine A, plakortamine B, lucartamides D, plakortamine C, eudistomidines, trectandramine, fascaplisin and/or salts, derivatives, hydrate or solvate and/or combinations thereof.
I ?carotenoidi?, chiamati anche ?tetraterpenoidi?, sono pigmenti organici gialli, arancioni e rossi che vengono prodotti da piante e alghe, nonch? diversi batteri e funghi. I carotenoidi possono essere inoltre categorizzati in due classi, xantofille (che contengono ossigeno) e caroteni (che sono semplicemente idrocarburi e non contengono ossigeno). Esempi di caroteni sono ?-carotene, ?-carotene, licopene, astaxantina e zeaxantina. Tutti i carotenoidi sono derivati di tetraterpeni, il che significa che vengono prodotti da 8 molecole di isoprene e contengono 40 atomi di carbonio. In generale, i carotenoidi assorbono lunghezze d?onda che vanno da 400 a 550 nanometri (luce da violetta a verde).Carotenoids, also called tetraterpenoids, are yellow, orange, and red organic pigments that are produced by plants and algae, as well as various bacteria and fungi. Carotenoids can be further categorized into two classes, xanthophylls (which contain oxygen) and carotenes (which are simply hydrocarbons and do not contain oxygen). Examples of carotenes are ?-carotene, ?-carotene, lycopene, astaxanthin, and zeaxanthin. All carotenoids are derivatives of tetraterpenes, which means they are made from 8 isoprene molecules and contain 40 carbon atoms. In general, carotenoids absorb wavelengths ranging from 400 to 550 nanometers (violet to green light).
Carotenoidi che contengono anelli di beta-ionone non sostituiti (inclusi ?carotene, ?-carotene, ?-criptoxantina e ?-carotene) hanno attivit? di vitamina A (il che significa che possono essere convertiti in retinolo).Carotenoids that contain unsubstituted beta-ionone rings (including ?-carotene, ?-carotene, ?-cryptoxanthin, and ?-carotene) have vitamin A activity (meaning they can be converted to retinol).
Preferibilmente, i carotenoidi usati nella presente invenzione sono ottenuti mediante estrazione vegetale e/o fermentazione microbica.Preferably, the carotenoids used in the present invention are obtained by plant extraction and/or microbial fermentation.
SOMMARIO DELL?INVENZIONESUMMARY OF THE INVENTION
La presente invenzione si riferisce a nuovi composti triptamminici non allucinogeni di formula I e/o formula II:The present invention relates to novel non-hallucinogenic tryptamine compounds of formula I and/or formula II:
. L?invenzione si riferisce anche a un processo per la preparazione di composti di formula I o II comprendente una fase di coniugazione di una porzione chimica non idrolizzabile con precursori triptamminici, che possono essere ottenuti in modo sintetico, e che sono analoghi a triptammine presenti naturalmente in funghi contenenti psilocibina, preferibilmente in funghi contenenti psilocibina appartenenti al genere Psilocybe.. The invention also relates to a process for the preparation of compounds of formula I or II comprising a conjugation step of a non-hydrolysable chemical moiety with tryptamine precursors, which can be obtained synthetically, and which are analogous to tryptamines naturally present in psilocybin-containing mushrooms, preferably in psilocybin-containing mushrooms belonging to the genus Psilocybe.
Inoltre, l?invenzione si riferisce a una composizione comprendente almeno uno di detti composti triptamminici non allucinogeni di formula I e/o formula II, opzionalmente in combinazione con almeno un composto di inibitori delle monoammino ossidasi (MAOI) e/o con almeno un antiossidante selezionato tra carotenoidi.Furthermore, the invention relates to a composition comprising at least one of said non-hallucinogenic tryptamine compounds of formula I and/or formula II, optionally in combination with at least one monoamine oxidase inhibitor (MAOI) compound and/or with at least one antioxidant selected from carotenoids.
Un ulteriore scopo dell?invenzione sono i composti di formula I e/o formula Il secondo la rivendicazione 1 per uso come medicinale.A further object of the invention are the compounds of formula I and/or formula II according to claim 1 for use as a medicinal product.
Infine, l?invenzione si riferisce ai composti secondo la formula I e/o II e alla composizione che li contiene, per uso nel trattamento di fibromialgia, dolore neuropatico cronico indotto da lesione del midollo spinale, dolore neuropatico associato a neuropatia periferica diabetica, nevralgia posterpetica, dolore muscoloscheletrico cronico e/o una malattia infiammatoria indotta da TNF-?.Finally, the invention relates to the compounds according to formula I and/or II and to the composition containing them, for use in the treatment of fibromyalgia, chronic neuropathic pain induced by spinal cord injury, neuropathic pain associated with diabetic peripheral neuropathy, postherpetic neuralgia, chronic musculoskeletal pain and/or a TNF-α-induced inflammatory disease.
Secondo una forma di realizzazione preferita, la malattia infiammatoria indotta da TNF-? ? selezionata tra artrite reumatoide, artrite idiopatica giovanile, artrite psoriasica, spondilite anchilosante, morbo di Crohn.According to a preferred embodiment, the inflammatory disease induced by TNF-? is selected from rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn's disease.
DESCRIZIONE DETTAGLIATADETAILED DESCRIPTION
La presente invenzione si riferisce a nuovi composti triptamminici non allucinogeni di formula I e/o formula II:The present invention relates to novel non-hallucinogenic tryptamine compounds of formula I and/or formula II:
,,
in cui:in which:
- A ? -NR1R2 o -N<+>R1R2R3;- A ? -NR1R2 or -N<+>R1R2R3;
- R1, R2 e R3 sono ciascuno indipendentemente selezionati dal gruppo consistente di H, CH3 o un gruppo alchile, preferibilmente selezionati tra C2H5, C3H7 e (CH3)2CH;- R1, R2 and R3 are each independently selected from the group consisting of H, CH3 or an alkyl group, preferably selected from C2H5, C3H7 and (CH3)2CH;
- il gruppo (OCH2CH2)n ? oligo- o polietilen glicole, in cui preferibilmente n ? selezionato tra 50 e 1, pi? preferibilmente n ? selezionato tra 11 e 3;- the group (OCH2CH2)n is oligo- or polyethylene glycol, wherein preferably n is selected between 50 and 1, more preferably n is selected between 11 and 3;
- X ? selezionato dal gruppo consistente di H, Me, CH2CH2NH2, CH2CH2SH, CH2CH2COOH, alogeno o CH2CH2PO(OH)2, con la condizione che X non pu? essere H nella struttura I;- X is selected from the group consisting of H, Me, CH2CH2NH2, CH2CH2SH, CH2CH2COOH, halogen or CH2CH2PO(OH)2, with the condition that X cannot be H in structure I;
- Y ? un distanziatore C1-C10 alchilico, preferibilmente un distanziatore C1C4 alchilico, opzionalmente contenente ossigeno, azoto, zolfo, 1,2,3-triazolo e/o un?ulteriore catena di oligo- o polietilen glicole;- Y ? a C1-C10 alkyl spacer, preferably a C1C4 alkyl spacer, optionally containing oxygen, nitrogen, sulfur, 1,2,3-triazole and/or an additional oligo- or polyethylene glycol chain;
e/o sali, derivati, idrato o solvato farmaceuticamente accettabili e/o combinazioni relative.and/or pharmaceutically acceptable salts, derivatives, hydrate or solvate and/or combinations thereof.
I composti di formula I o formula II possono essere ottenuti usando un processo comprendente una fase di coniugazione di una porzione chimica non idrolizzabile con precursori triptamminici, che possono essere ottenuti in modo sintetico, e che sono analoghi a triptammine presenti naturalmente in funghi contenenti psilocibina, preferibilmente in funghi contenenti psilocibina appartenenti al genere Psilocybe. La porzione chimica non idrolizzabile viene selezionata tra:Compounds of formula I or formula II may be obtained using a process comprising a conjugation step of a non-hydrolysable chemical moiety with tryptamine precursors, which may be obtained synthetically, and which are analogous to tryptamines naturally occurring in psilocybin-containing mushrooms, preferably in psilocybin-containing mushrooms belonging to the genus Psilocybe. The non-hydrolysable chemical moiety is selected from:
in cui:in which:
- il gruppo (OCH2CH2)n ? oligo- o polietilen glicole, in cui preferibilmente n ? selezionato tra 50 e 1, pi? preferibilmente n ? selezionato tra 11 e 3;- the group (OCH2CH2)n is oligo- or polyethylene glycol, wherein preferably n is selected between 50 and 1, more preferably n is selected between 11 and 3;
- X ? selezionato dal gruppo consistente di H, Me, CH2CH2NH2, CH2CH2SH, CH2CH2COOH, alogeno o CH2CH2PO(OH)2, con la condizione che X non pu? essere H nella struttura I; e- X is selected from the group consisting of H, Me, CH2CH2NH2, CH2CH2SH, CH2CH2COOH, halogen, or CH2CH2PO(OH)2, with the proviso that X cannot be H in structure I; and
- Y ? un distanziatore C1-C10 alchilico, preferibilmente un distanziatore C1-C4 alchilico, opzionalmente contenente ossigeno, azoto, zolfo, 1,2,3-triazolo e/o un?ulteriore catena di oligo- o polietilen glicole.- Y ? a C1-C10 alkyl spacer, preferably a C1-C4 alkyl spacer, optionally containing oxygen, nitrogen, sulfur, 1,2,3-triazole and/or an additional oligo- or polyethylene glycol chain.
Secondo una forma di realizzazione preferita, funghi contenenti psilocibina appartenenti al genere Psilocybe comprendono Psilocybe atlantis, Psilocybe azurenscens, Psilocybe bohemica, Psylocibe baeocystis, Psilocybe cyanescens, Psilocybe cubensis, Psilocybe tampanensis, Psilocybe hoogshagenii Psilocybe mexicana, Psilocybe ovoideocystidiata, Psilocybe semilanceata Psilocybe weraroa, Psilocybe stuntzii, Psilocybe cyanofibrillosa, Psilocybe zapotacorum, Psilocybe yungensis, Psilocybe liniformans, Psilocybe xalapensis, Psilocybe venenata, Psilocybe subtropicalis, Psilocybe singer, Psilocybe schultesii, Psilocybe rostrata, Psilocybe quebecensis, Psilocybe pintonii, Psilocybe puberula, Psilocybe mairei, Psilocybe laurae, Psilocybe kumaenorum, Psilocy beheimii, Psilocy begalindoi, Psilocybe fmetaria, Psilocy beegonii, Psilocybe dumontii, Psilocybe carbonaria, Psilocybe cordispora, Psilocybe bispora, Psilocybe aucklandii, e combinazioni relative.In a preferred embodiment, psilocybin-containing mushrooms belonging to the genus Psilocybe include Psilocybe atlantis, Psilocybe azurenscens, Psilocybe bohemica, Psilocybe baeocystis, Psilocybe cyanescens, Psilocybe cubensis, Psilocybe tampanensis, Psilocybe hoogshagenii, Psilocybe mexicana, Psilocybe ovoideocystidiata, Psilocybe semilanceata, Psilocybe weraroa, Psilocybe stuntzii, Psilocybe cyanofibrillosa, Psilocybe zapotacorum, Psilocybe yungensis, Psilocybe liniformans, Psilocybe xalapensis, Psilocybe venenata, Psilocybe subtropicalis, Psilocybe singer, Psilocybe schultesii, Psilocybe rostrata, Psilocybe quebecensis, Psilocybe pintonii, Psilocybe puberula, Psilocybe mairei, Psilocybe laurae, Psilocybe kumaenorum, Psilocy beheimii, Psilocy begalindoi, Psilocybe fmetaria, Psilocy beegonii, Psilocybe dumontii, Psilocybe carbonaria, Psilocybe cordispora, Psilocybe bispora, Psilocybe aucklandii, and related combinations.
La porzione chimica non idrolizzabile descritta in precedenza, nello specifico oligo- o polietilen glicole opzionalmente funzionalizzato e opzionalmente contenente un distanziatore, rende i composti triptamminici di formula I e/o II incapaci di attraversare la barriera emato-encefalica (BBB). Pertanto, l?attivit? farmacologica di composti triptamminici di formula I e/o II si verifica soltanto a livello periferico, nello specifico su recettori della 5-HT2A periferici, evitando in questo modo un effetto secondario indesiderato su sistemi nervosi centrali, come allucinazioni.The non-hydrolysable chemical moiety described above, specifically optionally functionalised oligo- or polyethylene glycol and optionally containing a spacer, renders tryptamine compounds of formula I and/or II incapable of crossing the blood-brain barrier (BBB). Therefore, the pharmacological activity of tryptamine compounds of formula I and/or II occurs only peripherally, specifically on peripheral 5-HT2A receptors, thus avoiding an undesirable secondary effect on central nervous systems, such as hallucinations.
In considerazione di quanto sopra, i composti di formula I e/o formula II secondo la rivendicazione 1 possono essere usati come medicinale, in particolare sono farmaci anti-infiammatori non allucinogeni, utili nel trattamento di fibromialgia, dolore neuropatico cronico indotto da lesione del midollo spinale, dolore neuropatico associato a neuropatia periferica diabetica, nevralgia post-erpetica, dolore muscoloscheletrico cronico e/o una malattia infiammatoria indotta da TNF-?.In view of the above, the compounds of formula I and/or formula II according to claim 1 can be used as a medicinal product, in particular they are non-hallucinogenic anti-inflammatory drugs, useful in the treatment of fibromyalgia, chronic neuropathic pain induced by spinal cord injury, neuropathic pain associated with diabetic peripheral neuropathy, post-herpetic neuralgia, chronic musculoskeletal pain and/or a TNF-α-induced inflammatory disease.
Secondo una forma di realizzazione preferita, la malattia infiammatoria indotta da TNF-? ? selezionata tra artrite reumatoide, artrite idiopatica giovanile, artrite psoriasica, spondilite anchilosante, morbo di Crohn.According to a preferred embodiment, the inflammatory disease induced by TNF-? is selected from rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn's disease.
Uno scopo della presente invenzione ? anche una composizione comprendente almeno un composto triptamminico non allucinogeno di formula I e/o formula II descritto in precedenza.An object of the present invention is also a composition comprising at least one non-hallucinogenic tryptamine compound of formula I and/or formula II described above.
Secondo una forma di realizzazione preferita, la composizione secondo l?invenzione comprende inoltre almeno un composto MAOI, per inibire la degradazione metabolica e la clearance dei composti triptamminici non allucinogeni di formula I e/o formula II.According to a preferred embodiment, the composition according to the invention further comprises at least one MAOI compound, to inhibit the metabolic degradation and clearance of non-hallucinogenic tryptamine compounds of formula I and/or formula II.
Le monoammino ossidasi (MAO) sono enzimi metabolici attaccati al lato citosolico della membrana esterna dei mitocondri delle cellule neuronali, gliali e di vario tipo. In particolare, catalizzano la deaminazione ossidativa di composti biogenici neuroattivi e vasoattivi (incluse serotonina e triptammine) e ammine xenobiotiche nelle corrispondenti aldeide e ammoniaca, sia nel sistema nervoso centrale sia nei tessuti periferici. Diversi inibitori delle monoammino ossidasi (MAOI) sono stati ampiamente impiegati come antidepressivi e agenti neuroprotettivi nel morbo di Parkinson, nonch? nel trattamento dell'ansia. Esistono due isoforme principali, MAO-A e MAO-B. La monoammino ossidasi A ? principalmente responsabile del metabolismo della psilocina (Reniers et al., ?Synthesis and evaluation of ?-carboline derivatives as potential monoamine oxidase inhibitors?, Bioorg. Med. Chem. (2011) v.19(1), pagg. 134-44).Monoamine oxidases (MAOs) are metabolic enzymes attached to the cytosolic side of the outer membrane of the mitochondria of neuronal, glial, and other cells. Specifically, they catalyze the oxidative deamination of neuroactive and vasoactive biogenic compounds (including serotonin and tryptamines) and xenobiotic amines to the corresponding aldehydes and ammonia, both in the central nervous system and peripheral tissues. Several monoamine oxidase inhibitors (MAOIs) have been widely used as antidepressants and neuroprotective agents in Parkinson's disease, as well as in the treatment of anxiety. There are two major isoforms, MAO-A and MAO-B. Monoamine oxidase A is the major isoform of MAO-A. mainly responsible for the metabolism of psilocin (Reniers et al., ?Synthesis and evaluation of ?-carboline derivatives as potential monoamine oxidase inhibitors?, Bioorg. Med. Chem. (2011) v.19(1), pages 134-44).
Secondo una forma di realizzazione preferita, l?almeno un composto MAOI che pu? essere opzionalmente addizionato alla composizione secondo l?invenzione ? selezionato dal gruppo consistente di norarmano, perlolirina, armolo, cordisinine tetraidroarmina, 6-metossiarmalano, armalano, armalina, armalolo, diidro-?-carboline (DH?C), tetraidro-?-carbolina (TH?C), metil-tetraidro-?-carbolina MTH?C, pinolina, 1-triclorometil-1,2,3,4-tetraidro-b-carbolina (TaClo), 6-metossitetraidroarmalano, etil ?-carbolin-3-carbossilato (?CCE), ?-carbolin-3-carbossilato (?CCM), manzamina A, manzamina X, 6-deossimanzamina X, manzamina Y, 8-idrossimanzamina A, 8-metossimanzamina A, 6-idrossimanzamina A, 3,4-diidromanzamina A, ent-8-idrossimanzamina A, ent-manzamina F, neo-kauluamina, xestomanzamina B, irtioerectine A, gesashidina A, plakortamine A, plakortamine B, lucartamidi D, plakortamine C, eudistomidine, trectandramina o fascaplisina e/o sali, derivati, idrato o solvato e/o combinazioni relative.According to a preferred embodiment, the at least one MAOI compound that can be optionally added to the composition according to the invention is selected from the group consisting of norharman, perlolyrin, harmol, cordisinin tetrahydroharmine, 6-methoxyharmalan, harmalane, harmaline, harmalol, dihydro-?-carboline (DH?C), tetrahydro-?-carboline (TH?C), methyl-tetrahydro-?-carboline MTH?C, pinoline, 1-trichloromethyl-1,2,3,4-tetrahydro-b-carboline (TaClo), 6-methoxytetrahydroharmalan, ethyl ?-carboline-3-carboxylate (?CCE), ?-carboline-3-carboxylate (?CCM), manzamine A, manzamine X, 6-deoxymizantamine X, manzamine Y, 8-hydroxymanzamine A, 8-methoxymizantamine A, 6-hydroxymanzamine A, 3,4-dihydromanzamine A, ent-8-hydroxymanzamine A, ent-manzamine F, neo-kauluamine, xestomanzamine B, irtioerectine A, gesashidin A, plakortamine A, plakortamine B, lucartamides D, plakortamine C, eudistomidines, trectandramine or fascaplisin and/or salts, derivatives, hydrate or solvate and/or combinations thereof.
Secondo un?ulteriore forma di realizzazione preferita, l?almeno un MAOI ? selezionato tra norarmano, perlolirina, armolo, cordisinine tetraidroarmina e/o sali, derivati, idrato, o solvato e/o combinazioni relative.According to a further preferred embodiment, the at least one MAOI is selected from norharman, perlolyrin, harmol, cordisinin, tetrahydroharmine and/or salts, derivatives, hydrate, or solvate and/or combinations thereof.
Inoltre, la composizione dell?invenzione pu? anche comprendere almeno un antiossidante selezionato tra carotenoidi, preferibilmente selezionato tra carotenoidi ottenuti mediante estrazione vegetale e/o fermentazione microbica.Furthermore, the composition of the invention may also comprise at least one antioxidant selected from carotenoids, preferably selected from carotenoids obtained by plant extraction and/or microbial fermentation.
Secondo un?ulteriore forma di realizzazione preferita, l?almeno un antiossidante selezionato tra carotenoidi ? ?-carotene, ?-carotene, licopene, astaxantina e/o zeaxantina.According to a further preferred embodiment, the at least one antioxidant selected from carotenoids ?-carotene, ?-carotene, lycopene, astaxanthin and/or zeaxanthin.
Il rapporto molare tra l?almeno un composto triptamminico non allucinogeno di formula I e/o formula II secondo l?invenzione e l?almeno un composto MAOI, preferibilmente selezionato tra norarmano, perlolirina, armolo, cordisinine tetraidroarmina, 6-metossiarmalano, armalano, armalina, armalolo, diidro-?-carboline (DH?C), tetraidro-?-carbolina (TH?C), metiltetraidro-?-carbolina MTH?C, pinolina, 1-triclorometil-1,2,3,4-tetraidro-bcarbolina (TaClo), 6-metossitetraidroarmalano, etil ?-carbolin-3-carbossilato (?CCE), ?-carbolin-3-carbossilato (?CCM), manzamina A, manzamina X, 6-deossimanzamina X, manzamina Y, 8-idrossimanzamina A, 8-metossimanzamina A, 6-idrossimanzamina A, 3,4-diidromanzamina A, ent-8-idrossimanzamina A, ent-manzamina F, neo-kauluamina, xestomanzamina B, irtioerectine A, gesashidina A, plakortamine A, plakortamine B, lucartamidi D, plakortamine C, eudistomidine, trectandramina, fascaplisina e/o sali, derivati, idrato o solvato e/o combinazioni relative ? compreso tra circa 10 : 1 e circa 1 : 10, preferibilmente compreso tra circa 100 : 1 e circa 1 : 100, pi? preferibilmente compreso tra circa 1.000 : 1 e circa 1 : 1.000 e inoltre pi? preferibilmente compreso tra 10.000 : 1 e circa 1 : 10.000.The molar ratio of the at least one non-hallucinogenic tryptamine compound of formula I and/or formula II according to the invention and the at least one MAOI compound, preferably selected from norharman, perlolyrin, harmol, cordisinine tetrahydroharmine, 6-methoxyharmalan, harmalane, harmaline, harmalol, dihydro-?-carbolines (DH?C), tetrahydro-?-carboline (TH?C), methyltetrahydro-?-carboline MTH?C, pinoline, 1-trichloromethyl-1,2,3,4-tetrahydro-bcarboline (TaClo), 6-methoxytetrahydroharmalan, ethyl ?-carboline-3-carboxylate (?CCE), ?-carboline-3-carboxylate (?CCM), manzamine A, manzamine X, 6-deoxymizantamine X, manzamine Y, 8-hydroxymanzamine A, 8-methoxymanzamine A, 6-hydroxymanzamine A, 3,4-dihydromanzamine A, ent-8-hydroxymanzamine A, ent-manzamine F, neo-kauluamine, xestomanzamine B, irtioerectin A, gesashidin A, plakortamine A, plakortamine B, lucartamides D, plakortamine C, eudistomidines, trectandramine, fascaplisin and/or salts, derivatives, hydrate or solvate and/or combinations thereof is between about 10 : 1 and about 1 : 10, preferably between about 100 : 1 and about 1 : 100, more preferably between about 1,000 : 1 and about 1 : 1,000 and furthermore more preferably between 10,000 : 1 and approximately 1 : 10,000.
Secondo un?ulteriore forma di realizzazione preferita, la composizione dell?invenzione comprende anche almeno un antiossidante selezionato tra carotenoidi, preferibilmente selezionato tra carotenoidi ottenuti mediante estrazione vegetale e/o fermentazione microbica. Pi? preferibilmente, l?almeno un antiossidante selezionato tra carotenoidi ? ?-carotene, ?carotene, licopene, astaxantina e/o zeaxantina.According to a further preferred embodiment, the composition of the invention also comprises at least one antioxidant selected from carotenoids, preferably selected from carotenoids obtained by plant extraction and/or microbial fermentation. More preferably, the at least one antioxidant selected from carotenoids is ?-carotene, ?-carotene, lycopene, astaxanthin and/or zeaxanthin.
La composizione dell?invenzione pu? essere usata nel trattamento di fibromialgia, dolore neuropatico cronico indotto da lesione del midollo spinale, dolore neuropatico associato a neuropatia periferica diabetica, nevralgia post-erpetica, dolore muscoloscheletrico cronico e/o una malattia infiammatoria indotta da TNF-?. Secondo una forma di realizzazione preferita, la malattia infiammatoria indotta da TNF-? ? selezionata tra artrite reumatoide, artrite idiopatica giovanile, artrite psoriasica, spondilite anchilosante, morbo di Crohn, colite ulcerosa, psoriasi a placche, idrosadenite suppurativa e/o uveite.The composition of the invention may be used in the treatment of fibromyalgia, chronic neuropathic pain induced by spinal cord injury, neuropathic pain associated with diabetic peripheral neuropathy, post-herpetic neuralgia, chronic musculoskeletal pain and/or a TNF-?-induced inflammatory disease. According to a preferred embodiment, the TNF-?-induced inflammatory disease is selected from rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn's disease, ulcerative colitis, plaque psoriasis, hidradenitis suppurativa and/or uveitis.
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| PCT/IB2023/063185WO2024134619A1 (en) | 2022-12-23 | 2023-12-22 | Non-hallucinogenic tryptamine compounds, preparation, pharmaceutical compositions and uses thereof |
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| WO2003032990A2 (en) | 2001-10-18 | 2003-04-24 | Nektar Therapeutics Al, Corporation | Polymer conjugates of opioid antagonists |
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