IT202000031025A1 - ENZYMATIC PROCESS FOR THE PREPARATION OF ESTERS OF POORLY WATER-SOLUBLE CARBOXYLIC ACIDS. - Google Patents
ENZYMATIC PROCESS FOR THE PREPARATION OF ESTERS OF POORLY WATER-SOLUBLE CARBOXYLIC ACIDS. Download PDFInfo
- Publication number
- IT202000031025A1 IT202000031025A1 IT102020000031025A IT202000031025A IT202000031025A1 IT 202000031025 A1 IT202000031025 A1 IT 202000031025A1 IT 102020000031025 A IT102020000031025 A IT 102020000031025A IT 202000031025 A IT202000031025 A IT 202000031025A IT 202000031025 A1 IT202000031025 A1 IT 202000031025A1
- Authority
- IT
- Italy
- Prior art keywords
- acid
- ester
- sorbitol
- erythritol
- xylitol
- Prior art date
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P7/00—Preparation of oxygen-containing organic compounds
- C12P7/62—Carboxylic acid esters
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
- C12N9/14—Hydrolases (3)
- C12N9/16—Hydrolases (3) acting on ester bonds (3.1)
- C12N9/18—Carboxylic ester hydrolases (3.1.1)
- C12N9/20—Triglyceride splitting, e.g. by means of lipase
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Y—ENZYMES
- C12Y301/00—Hydrolases acting on ester bonds (3.1)
- C12Y301/01—Carboxylic ester hydrolases (3.1.1)
- C12Y301/01003—Triacylglycerol lipase (3.1.1.3)
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- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
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- Engineering & Computer Science (AREA)
- Genetics & Genomics (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Engineering & Computer Science (AREA)
- Medicinal Chemistry (AREA)
- Biochemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Microbiology (AREA)
- Biotechnology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Chemical & Material Sciences (AREA)
- Molecular Biology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Rheumatology (AREA)
- Pain & Pain Management (AREA)
- Biomedical Technology (AREA)
- Epidemiology (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
Processo enzimatico per la preparazione di esteri di acidi carbossilici scarsamente solubili in acqua Enzymatic process for the preparation of poorly water soluble carboxylic acid esters
La presente invenzione riguarda un processo enzimatico per la preparazione di esteri di acidi carbossilici scarsamente solubili in acqua. In particolare, la presente invenzione riguarda un processo enzimatico per la preparazione di esteri di acidi carbossilici scarsamente solubili in acqua con una molecola portatrice di un gruppo idrossilico in un sistema di reazione monofasico. The present invention relates to an enzymatic process for the preparation of poorly water soluble carboxylic acid esters. In particular, the present invention relates to an enzymatic process for the preparation of poorly water-soluble carboxylic acid esters with a molecule carrying a hydroxyl group in a monophasic reaction system.
? noto come la traslazione di farmaci scarsamente idrosolubili in prodotti medicinali efficaci sia una continua sfida [1]. Pi? del 40% delle nuove entit? chimiche (NCE) che possiedono attivit? farmacologiche, sintetizzate da programmi di screening combinatorio superiori, sono scarsamente solubili, il che ? un grande ostacolo allo sviluppo delle formulazioni [2][3]. Pertanto, i farmaci con scarsa solubilit? in acqua richiedono nuovi approcci di formulazione per migliorare i loro tassi di dissoluzione e biodisponibilit? orale [4]. Spesso, la solubilit? di questi farmaci ? limitata nello stomaco per via della presenza di un acido carbossilico in un mezzo acido acquoso [5]. Per questo motivo, un modo per aumentare l'idrosolubilit? delle forme di farmaci scarsamente solubili in acqua potrebbe essere una reazione di esterificazione tra il suo acido carbossilico e un alcol per ottenere un farmaco dalla potenziata idrosolubilit?, progettato per avere una migliore disponibilit? orale [6]. Questo tipo di modifica potrebbe portare a sintetizzare un profarmaco. Un profarmaco ? un composto che ha la capacit? di subire biotrasformazione prima di esibire le sue propriet? farmacologiche [7]. ? It is known that the translation of poorly water-soluble drugs into effective medicinal products is an ongoing challenge [1]. Pi? of 40% of the new entities? chemical (NCE) that possess activity? pharmacological, synthesized by superior combinatorial screening programs, are poorly soluble, which ? a major obstacle to formulation development [2][3]. Therefore, drugs with poor solubility in water require new formulation approaches to improve their dissolution rates and bioavailability? oral [4]. Often, the solubility of these drugs? limited in the stomach due to the presence of a carboxylic acid in an aqueous acidic medium [5]. For this reason, one way to increase water solubility is Poorly water-soluble drug forms could be an esterification reaction between its carboxylic acid and an alcohol to yield a drug with enhanced water solubility, designed to have better water availability. oral [6]. This type of modification could lead to the synthesis of a prodrug. A prodrug? a compound that has the ability? to undergo biotransformation before exhibiting its properties? pharmacological [7].
Canonicamente, la reazione di esterificazione viene eseguita chimicamente mediante esterificazione di Fischer [8]. A differenza delle modificazioni chimiche, gli approcci biotecnologici possono rappresentare una via ?green? per la sintesi di derivati bioattivi dei farmaci [9][10]. I processi ?green? devono utilizzare catalizzatori ecologici, non tossici e riutilizzabili per sintetizzare composti chimici di valore [11]. Ad esempio, l'ibuprofene ? un farmaco scarsamente solubile in acqua. La sua esterificazione con composti idrofili consente quindi di ottenere una molecola di sintesi potenziata nella sua idrosolubilit? e conseguente biodisponibilit?. Questa strategia pu? essere sviluppata tramite una reazione di esterificazione bio-catalizzata. A questo scopo le lipasi rappresentano lo strumento biologico pi? utilizzato per l'esterificazione enzimatica. Dagli anni novanta, le lipasi (triacilglicerolo idrolasi, EC 3.1.1.3) sono state utilizzate come biocatalizzatori nelle industrie per via della loro attivit? in blande condizioni di reazione, la mancanza di necessit? di cofattori, la loro attivit? sintetica in solventi non acquosi e la loro ampia gamma di substrati stereospecifici [12]. Le lipasi sono ampiamente utilizzate come biocatalizzatori per reazioni di esterificazione o transesterificazione ed esistono libere o in forma immobilizzata [13]. Tra le lipasi non immobilizzate (libere) pi? comunemente utilizzate per le reazioni di esterificazione o transesterificazione ci sono quelle dei microrganismi R. miehei [14], C. rugosa [15] and P. cepacian [16]. Lipasi immobilizzate, come Novozyme 435 (C. antarctica lipasi tipo B, CALB) [17], Lipozyme RM-IM (lipasi da R. miehei) e Lipozyme TL-IM (lipase from T. lanuginosus) [18] sono anch?esse disponibili in commercio. Canonically, the esterification reaction is performed chemically by Fischer esterification [8]. Unlike chemical modifications, biotechnological approaches can represent a ?green? for the synthesis of bioactive derivatives of drugs [9][10]. The ?green? processes they must use environmentally friendly, non-toxic and reusable catalysts to synthesize valuable chemical compounds [11]. For example, ibuprofen ? a poorly water soluble drug. Its esterification with hydrophilic compounds therefore allows to obtain a synthetic molecule enhanced in its water solubility. and consequent bioavailability. This strategy can be developed via a bio-catalyzed esterification reaction. For this purpose, the lipases represent the most biological tool? used for enzymatic esterification. Since the 1990s, lipases (triacylglycerol hydrolase, EC 3.1.1.3) have been used as biocatalysts in industries due to their active activity. in mild reaction conditions, the lack of need? of cofactors, their activity? synthetic in non-aqueous solvents and their wide range of stereospecific substrates [12]. Lipases are widely used as biocatalysts for esterification or transesterification reactions and exist free or in immobilized form [13]. Among the non-immobilized (free) lipases more? commonly used for esterification or transesterification reactions are those of the microorganisms R. miehei [14], C. rugosa [15] and P. cepacian [16]. Immobilized lipases, such as Novozyme 435 (C. antarctica lipase type B, CALB) [17], Lipozyme RM-IM (lipase from R. miehei) and Lipozyme TL-IM (lipase from T. lanuginosus) [18] are also commercially available.
Le lipasi sono molecole idrofile con un sito attivo compreso in una tasca idrofobica. Tale tasca idrofobica ? ricoperta da una catena polipeptidica chiamata coperchio (?lid?), che generalmente isola il sito attivo dal mezzo di reazione (in questa forma chiusa la lipasi ? inattiva). Il coperchio ha anche una faccia idrofoba interna che interagisce con le aree idrofobiche del sito attivo ed una faccia esterna idrofila, che interagisce con il mezzo di reazione. Questo coperchio pu? spostarsi formando una grande tasca idrofobica che espone il centro attivo al mezzo, dando luogo alla forma ?aperta? e attiva della lipasi, con la fase idrofila del coperchio che interagisce con la superficie della proteina. In un ambiente di reazione le lipasi subiscono l?attivazione interfacciale a causa di una polarit? opposta tra l?enzima (idrofilo) ed i substrati (lipofili). La reazione avviene all?interfaccia tra la fase acquosa e quella oleosa, dove si verifica un cambiamento conformazionale associato ad una aumentata attivit? enzimatica. Le interfacce risultano pertanto dei punti chiave per la biocatalisi della lipasi ed un sito appropriato per modulare l?attivit? della lipolisi [19]. Lipases are hydrophilic molecules with an active site enclosed in a hydrophobic pocket. This hydrophobic pocket ? covered by a polypeptide chain called lid (?lid?), which generally isolates the active site from the reaction medium (in this closed form the lipase is inactive). The lid also has an inner hydrophobic face which interacts with the hydrophobic areas of the active site and a hydrophilic outer face which interacts with the reaction medium. This lid can move forming a large hydrophobic pocket which exposes the active center to the medium, giving rise to the ?open? and active lipase, with the hydrophilic phase of the cap interacting with the protein surface. In a reaction environment, the lipases undergo interfacial activation due to a polarity? opposite between the enzyme (hydrophilic) and the substrates (lipophilic). The reaction takes place at the interface between the aqueous and oily phases, where a conformational change occurs associated with increased activity. enzymatic. The interfaces are therefore key points for the biocatalysis of the lipase and an appropriate site to modulate the activity of the lipase. of lipolysis [19].
L?uso di solventi in un sistema bifasico acquoso-organico pu? dunque indurre l?attivazione interfacciale della lipasi. Per migliorare la superficie dell?interfaccia ? consigliata una vigorosa miscelazione delle due fasi, che forma una sospensione dall?area interfacciale molto ampia. Spesso, tuttavia, l?ambiente bifasico pu? rappresentare anche un grande svantaggio. La presenza di acqua, infatti, porta inevitabilmente alla reazione di idrolisi dei nuovi esteri prodotti, in virt? dell?equilibrio stechiometrico deducibile dalla sottostante generica reazione di esterificazione tra un acido carbossilico ed un alcol, catalizzata da lipasi: The use of solvents in an aqueous-organic biphasic system can thus induce the interfacial activation of lipase. To improve the surface of the interface ? Vigorous mixing of the two phases is recommended, which forms a suspension with a very large interfacial area. Often, however, the biphasic environment can also represent a major disadvantage. The presence of water, in fact, inevitably leads to the hydrolysis reaction of the new esters produced, by virtue of of the stoichiometric equilibrium deducible from the underlying generic esterification reaction between a carboxylic acid and an alcohol, catalysed by lipase:
Un esempio specifico di farmaco scarsamente solubile ? l?ibuprofene. L?ibuprofene ((R,S)-2-(acido pisobutilfenil)-propionico) ? un tradizionale farmaco antinfiammatorio non steroideo (FANS) [20] sviluppato alla fine degli anni 60 [21] per il trattamento dei sintomi causati da artrite, quali gonfiore, dolore e rigidit? [22]. L?ibuprofene, come il ketoprofene, il flurbiprofene ed altri farmaci non steroidei, ? ampiamente utilizzato per le sue propriet? analgesiche, antinfiammatorie ed antipiretiche [23]. ? impiegato nel trattamento del dolore di lieve o moderata intensit?, nei casi di dismenorrea, mal di testa (emicrania inclusa), dolore dentale, dolore post-operatorio, disturbi muscoloscheletrici o articolari, inclusi l?artrosi, l?artrite reumatoide e la spondilite anchilosante [23][24]. Il meccanismo d?azione dell?ibuprofene in diversi contesti terapeutici ? ben consolidato. L?ibuprofene ? un inibitore reversibile non selettivo degli isoenzimi della ciclossigenasi (COX-1 e COX-2), responsabili della conversione lipasi-catalizzata dell?acido arachidonico in prostaglandine, inclusi trombossano e prostaciclina [25]. A causa del suo centro chirale, l?ibuprofene presenta due enantiomeri [26]. Tuttavia, ? documentato che l?attivit? terapeutica dell?ibuprofene ? principalmente attribuita all?enantiomero (S), che ? 160 volte pi? efficace dell?enantiomero (R) [27]. Considerando l?elevata compliance del paziente, l?efficacia dei costi, dei vincoli di sterilit? ridotti e della flessibilit?, la via di somministrazione pi? comune per l?ibuprofene ? quella orale [28] sotto forma di compresse, capsule rigide o granulati effervescenti con dosaggi pari a 200mg, 400mg, 800mg [29][30]. La dose ? di 200-400mg (5-10mg/kg nei bambini), ogni 4-6 ore fino ad un massimo di 1,2g al giorno negli adulti [31]. Data la sua solubilit? in acqua di 21mg/L [32]. L?ibuprofene ? un farmaco scarsamente solubile in acqua, caratterizzato da biodisponibilit? orale limitata dalla dissoluzione [34]. Il basso tasso di dissoluzione delle forme di dosaggio solide attualmente disponibili e la conseguente scarsa biodisponibilit? di una dose orale elevata [33] possono causare gravi effetti avversi indesiderati. La somministrazione orale cronica di FANS pu? causare danni alla mucosa gastrica, in particolare ulcerazione gastrica, sanguinamento e perforazione [34]. Esistono formulazioni con coniugati di sale di ibuprofene (ad esempio arginato, lisinato e sodio) con lo scopo di aumentare la velocit? di dissoluzione nello stomaco [35]. La solubilit? dell?ibuprofene ? limitata nello stomaco, perch? si tratta di un acido carbossilico in un mezzo acido acquoso [5]. Per questo motivo, un modo per aumentare la solubilit? in acqua dell?ibuprofene potrebbe essere una reazione di esterificazione tra il suo acido carbossilico ed un alcol per ottenere un profarmaco idrosolubile potenziato, progettato per avere una migliore biodisponibilit? orale [6]. Gi? nel 1980, uno studio tossicologico su diversi derivati e formulazioni dell?ibuprofene ha mostrato il profarmaco dell?ibuprofene estere guaiacolo come forma adatta per questo farmaco, avente ridotta tossicit? nel ratto [36]. La progettazione, la sintesi e la somministrazione di quattro profarmaci dell?ibuprofene e acido L-ascorbico mirati al cervello mostrano un aumento dei livelli di ibuprofene nello stesso sito [39]. Inoltre, la sintesi ed il test dell?estere aminoalcolico N,N-disostituito dell?ibuprofene hanno determinato una significativa riduzione dell?effetto ulcerogeno nello stomaco [40]. A specific example of a poorly soluble drug? ibuprofen. Ibuprofen ((R,S)-2-(pisobutylphenyl)-propionic acid) is a traditional non-steroidal anti-inflammatory drug (NSAID) [20] developed in the late 1960s [21] to treat symptoms caused by arthritis, such as swelling, pain and stiffness [22]. Ibuprofen, like ketoprofen, flurbiprofen and other non-steroidal drugs, is widely used for its properties analgesic, anti-inflammatory and antipyretic [23]. ? used in the treatment of pain of mild to moderate intensity, in cases of dysmenorrhea, headache (including migraine), dental pain, post-operative pain, musculoskeletal or joint disorders, including osteoarthritis, rheumatoid arthritis and spondylitis ankylosing [23][24]. The mechanism of action of ibuprofen in different therapeutic contexts? well established. The ibuprofen ? a non-selective reversible inhibitor of cyclooxygenase isoenzymes (COX-1 and COX-2), responsible for the lipase-catalyzed conversion of arachidonic acid to prostaglandins, including thromboxane and prostacyclin [25]. Due to its chiral center, ibuprofen has two enantiomers [26]. However, ? documented that the? activity? therapeutics of ibuprofen? mainly attributed to the enantiomer (S), which ? 160 times more efficacy of the (R)-enantiomer [27]. Considering the high patient compliance, cost effectiveness, sterility constraints? reduced and flexibility, the administration route pi? common for ibuprofen ? oral [28] in the form of tablets, hard capsules or effervescent granules with dosages of 200mg, 400mg, 800mg [29][30]. The dose? of 200-400mg (5-10mg/kg in children), every 4-6 hours up to a maximum of 1.2g per day in adults [31]. Given its solubility? in water of 21mg/L [32]. The ibuprofen ? a drug poorly soluble in water, characterized by bioavailability? oral limited by dissolution [34]. The low dissolution rate of currently available solid dosage forms and the resulting poor bioavailability? of a high oral dose [33] can cause serious undesirable adverse effects. Chronic oral administration of NSAIDs can cause damage to the gastric mucosa, especially gastric ulceration, bleeding and perforation [34]. There are formulations with salt conjugates of ibuprofen (for example arginate, lysinate and sodium) with the aim of increasing the speed? of dissolution in the stomach [35]. The solubility? of ibuprofen ? limited in the stomach, why? it is a carboxylic acid in an aqueous acidic medium [5]. For this reason, a way to increase the solubility? in water of ibuprofen could be an esterification reaction between its carboxylic acid and an alcohol to obtain an enhanced water-soluble prodrug, designed to have better bioavailability? oral [6]. Yeah? In 1980, a toxicological study of several ibuprofen derivatives and formulations showed the ibuprofen ester prodrug guaiacol as a suitable form for this drug, having reduced toxicity. in the rat [36]. The design, synthesis and administration of four prodrugs of ibuprofen and L-ascorbic acid targeting the brain show an increase in ibuprofen levels at the same site [39]. Furthermore, the synthesis and testing of the N,N-disubstituted amino alcohol ester of ibuprofen resulted in a significant reduction of the ulcerogenic effect in the stomach [40].
L'ibuprofene ? stato esterificato enzimaticamente con glicerolo in solventless-media ed ? stato riportato il modello cinetico [37]. Tuttavia, questo sistema presenta diverse limitazioni. La presenza di acqua limita la resa di conversione finale. Il glicerolo ? il polialcol pi? corto che si pu? attaccare per ottenere un profarmaco con una maggiore solubilit? ed ? l'unico polialcol in forma liquida. Quindi, questo processo di esterificazione in mezzi senza solventi ? sfruttabile solo per questo polialcol, ed ? completamente inutile per altri polialcol con una catena pi? lunga come: eritritolo, xilitolo e sorbitolo. Questi polialcol sono in forma solida, quindi devono essere solubilizzati per prendere parte alla reazione enzimatica. Tuttavia, per produrre esteri tra molecole altamente idrofile, come eritritolo, xilitolo e sorbitolo (logP: -1,86 / -3,36) e farmaci lipofili, come l'ibuprofene (logP: 3,75), la letteratura riporta sistemi bifasici solvente/acqua. Oltre agli svantaggi sopra riportati, non sono stati segnalati n? sistemi di esterificazione bifasici n? monofasici tra il suddetto polialcol e ibuprofene. Infatti, in queste condizioni, ? difficile una reazione enzimatica tra molecole di tale polarit? opposta. The ibuprofen? been esterified enzymatically with glycerol in solventless-media and ? The kinetic model has been reported [37]. However, this system has several limitations. The presence of water limits the final conversion yield. Glycerol? the polyalcohol pi? short that you can? attack to obtain a prodrug with greater solubility? and ? the only polyalcohol in liquid form. So, this esterification process in solventless media? usable only for this polyalcohol, and ? completely useless for other polyalcohols with a chain pi? long as: erythritol, xylitol and sorbitol. These polyalcohols are in solid form, so they must be solubilized to take part in the enzymatic reaction. However, to produce esters between highly hydrophilic molecules, such as erythritol, xylitol and sorbitol (logP: -1.86 / -3.36) and lipophilic drugs, such as ibuprofen (logP: 3.75), the literature reports biphasic systems solvent/water. In addition to the disadvantages listed above, no n? biphasic esterification systems n? monophasic between the aforementioned polyalcohol and ibuprofen. Indeed, in these conditions, ? difficult an enzymatic reaction between molecules of such polarity? opposite.
Alla luce di quanto sopra risulta quindi evidente la necessit? di fornire un processo per l'esterificazione enzimatica di acidi carbossilici scarsamente solubili in acqua che superi gli svantaggi dei processi noti. In the light of the above, it is therefore evident that the need to provide a process for the enzymatic esterification of poorly water soluble carboxylic acids which overcomes the drawbacks of the known processes.
Secondo la presente invenzione, viene fornito un processo che supera i limiti delle attuali strategie di esterificazione enzimatica e massimizza le rese. In particolare, il processo secondo la presente invenzione ? un processo di sintesi enzimatica catalizzata da lipasi in un sistema monofasico che supera i limiti del sistema bifasico canonico e produce un'efficace reazione di esterificazione tra acidi carbossilici scarsamente solubili in acqua, come alcuni farmaci, e molecole altamente idrofile, come i polialcol solidi. According to the present invention, a process is provided which overcomes the limitations of current enzymatic esterification strategies and maximizes yields. In particular, the process according to the present invention ? an enzymatic synthesis process catalyzed by lipase in a monophasic system which overcomes the limits of the canonical biphasic system and produces an effective esterification reaction between carboxylic acids which are poorly soluble in water, such as some drugs, and highly hydrophilic molecules, such as solid polyalcohols.
I vantaggi del processo della presente invenzione sono ad esempio: migliore solubilit? dei substrati e del prodotto, spostamento degli equilibri termodinamici (cio? avviene la sintesi invece dell'idrolisi), possibile uso dell'enzima direttamente in una fase enzimatica di un processo chimico, e solubilizzazione di composti idrofili e lipofili nella stessa fase organica. The advantages of the process of the present invention are for example: better solubility? of substrates and of the product, shift of the thermodynamic equilibria (that is, synthesis takes place instead of hydrolysis), possible use of the enzyme directly in an enzymatic phase of a chemical process, and solubilization of hydrophilic and lipophilic compounds in the same organic phase.
Il sistema monofasico secondo la presente invenzione ? molto pi? semplice in termini di gestione della reazione. Pertanto, ? necessario considerare molte meno variabili rispetto alle variabili nei sistemi bifasici. Nel processo della presente invenzione l'acqua non ? richiesta, e questo sposta l'equilibrio idrolisi/sintesi verso il comportamento sintetico della lipasi. L'uso di un enzima immobilizzato disponibile in commercio porta a una sintesi organica altamente riproducibile con elevata stereo- e regio-specificit?. Inoltre, l'enzima immobilizzato ? stabile e perfettamente separabile dal terreno per poter essere riutilizzato anche per pi? di 10 cicli. The single-phase system according to the present invention ? much more simple in terms of handling the reaction. Therefore, ? far fewer variables need to be considered than the variables in two-phase systems. In the process of the present invention the water is not required, and this shifts the hydrolysis/synthesis balance towards the synthetic behavior of the lipase. The use of a commercially available immobilized enzyme leads to a highly reproducible organic synthesis with high stereo- and regio-specificity. Furthermore, the immobilized enzyme ? stable and perfectly separable from the ground in order to be reused even for more? of 10 cycles.
Un esempio di enzimi adatti per il processo della presente invenzione sono le lipasi, come CALB. Poich? CALB manca di un coperchio (?lid?) che copre il sito attivo, non necessita di alcuna attivazione interfacciale, quindi, pu? essere utilizzato in un sistema monofasico come quello della presente invenzione. Altre lipasi adatte sono le lipasi da Thermomyces lanuginosa e Rhizomucor miehei, che sono considerate simili a CALB in termini di capacit? catalitica per diversi substrati. Inoltre, secondo la presente invenzione, non sono necessarie fasi preliminari di protezione dei gruppi funzionali (mentre queste fasi sono normalmente necessarie nella sintesi chimica, cio? sintesi non enzimatica) e non vengono utilizzati solventi tossici. A differenza di molte sintesi enzimatiche riportate in letteratura, che richiedono tempi di reazione anche di 1 settimana, il processo secondo la presente invenzione consente una resa di conversione che va dal 65 al 100% dopo sole 24 ore. I volumi di reazione sono piccoli: l'esterificazione pu? essere ottenuta anche in reattori o microreattori da 2-5 mL. Questo processo su piccola scala pu? essere facilmente ampliato. Il processo della presente invenzione fornisce vantaggiosamente un modo per solubilizzare due substrati, cio? l'acido carbossilico e la molecola portatrice di gruppi idrossilici come un polialcol, in un unico solvente organico. Pertanto, la molecola che trasporta il gruppo idrossile non ha bisogno di essere liquida. Questo sistema funziona a basse temperature (da 40 a 85 ? C), a pressione atmosferica e il reattore non viene riempito con azoto o altri gas. Inoltre, il metodo dell'invenzione mostra una grande flessibilit? su diversi substrati. Le condizioni di reazione specifiche del processo, oltre alla scelta del solvente organico e dell'enzima, quali processi preliminari di solubilizzazione, concentrazioni, temperature, agitazione, rapporto di concentrazione tra acido ed alcol contribuiscono all'ottimizzazione del processo della presente invenzione in confronto con lo stato dell'arte della sintesi enzimatica catalizzata da lipasi. An example of enzymes suitable for the process of the present invention are lipases, such as CALB. because CALB lacks a lid (?lid?) covering the active site, it doesn't need any interfacial activation, therefore, it can? be used in a one-phase system such as that of the present invention. Other suitable lipases are the lipases from Thermomyces lanuginosa and Rhizomucor miehei, which are considered similar to CALB in terms of their ability to catalytic for different substrates. Furthermore, according to the present invention, preliminary steps for protecting the functional groups are not necessary (while these steps are normally necessary in chemical synthesis, i.e. non-enzymatic synthesis) and no toxic solvents are used. Unlike many enzymatic syntheses reported in the literature, which require reaction times of even 1 week, the process according to the present invention allows a conversion yield ranging from 65 to 100% after only 24 hours. The reaction volumes are small: the esterification can? also be obtained in 2-5 mL reactors or microreactors. This small-scale process can be easily expanded. The process of the present invention advantageously provides a way to solubilize two substrates, i.e. the carboxylic acid and the hydroxyl group-carrying molecule such as a polyalcohol, in a single organic solvent. Therefore, the molecule carrying the hydroxyl group need not be liquid. This system works at low temperatures (40 to 85 ? C), at atmospheric pressure and the reactor is not filled with nitrogen or other gases. Furthermore, the method of the invention shows great flexibility? on different substrates. The specific reaction conditions of the process, in addition to the choice of organic solvent and enzyme, such as preliminary solubilization processes, concentrations, temperatures, stirring, acid to alcohol concentration ratio contribute to the optimization of the process of the present invention in comparison with the state of the art of lipase-catalyzed enzymatic synthesis.
In particolare, il processo dell'invenzione porta alla formazione catalizzata enzimaticamente del legame estereo tra l'acido carbossilico di una molecola bersaglio e il gruppo ossidrile di una molecola portatrice di gruppi ossidrilici come un alcol, anche in forma solida. Secondo la presente invenzione, una quantit? predeterminata di solvente organico (ad esempio alcol amilico terziario: da 3 a 5 mL) viene posta in un reattore asciutto. Il solvente agisce per solubilizzare sia l'acido carbossilico (ad esempio ibuprofene) che la molecola portatrice di gruppi idrossilici (ad esempio un polialcol) in un sistema monofasico. ? noto che la forma del reattore sia importante per evitare la rottura meccanica del catalizzatore, in particolare, il contatto tra le pareti del reattore e l'agitatore magnetico deve essere pressoch? nullo. L'agitatore magnetico pu? essere preferibilmente un magnete ?a croce? che pu? ridurre al minimo il contatto con il catalizzatore immobilizzato al fine di evitarne la distruzione. Per solubilizzare un composto altamente idrofilo (come: eritritolo, xilitolo o sorbitolo, ma anche acido ascorbico) nel solvente (ad esempio alcol t-amilico) senza aggiunta di acqua, ? necessario un passaggio preliminare: una quantit? predeterminata di polialcol (o altri tipi di molecole portati ossidrili: come l'acido ascorbico) viene accuratamente aggiunto al solvente, il reattore viene chiuso per evitare l'evaporazione del solvente (anche se il punto di ebollizione dell'alcol t-amilico ? di circa 102,4 ? C). Il reattore viene posto su un agitatore magnetico e il solvente viene riscaldato fino alla temperatura desiderata. La miscelazione vigorosa ad alta temperatura pu? aiutare la solubilizzazione del polialcol nel solvente come l'alcol t-amilico. In particular, the process of the invention leads to the enzymatically catalyzed formation of the ester bond between the carboxylic acid of a target molecule and the hydroxyl group of a molecule carrying hydroxyl groups such as an alcohol, even in solid form. According to the present invention, a quantity predetermined amount of organic solvent (e.g. tertiary amyl alcohol: 3 to 5 mL) is placed in a dry reactor. The solvent acts to solubilize both the carboxylic acid (e.g. ibuprofen) and the hydroxyl group-carrying molecule (e.g. a polyalcohol) in a one-phase system. ? is known that the shape of the reactor is important to avoid the mechanical breakage of the catalyst, in particular, the contact between the walls of the reactor and the magnetic stirrer must be almost? null. The magnetic stirrer can be preferably a ?cross? what can? minimize contact with the immobilized catalyst in order to avoid its destruction. To solubilize a highly hydrophilic compound (such as: erythritol, xylitol or sorbitol, but also ascorbic acid) in the solvent (for example t-amyl alcohol) without adding water, ? necessary a preliminary step: a quantity? predetermined amount of polyalcohol (or other types of hydroxyl borne molecules: such as ascorbic acid) is carefully added to the solvent, the reactor is closed to avoid evaporation of the solvent (even if the boiling point of t-amyl alcohol is about 102.4 ?C). The reactor is placed on a magnetic stirrer and the solvent is heated to the desired temperature. Vigorous mixing at high temperatures can aid in the solubilization of the polyalcohol in the solvent such as t-amyl alcohol.
Ad esempio, le temperature che possono essere utilizzate per la solubilizzazione di eritritolo, xilitolo e sorbitolo polialcolici sono mostrate di seguito: For example, the temperatures that can be used for the solubilization of polyalcohol erythritol, xylitol, and sorbitol are shown below:
- eritritolo: da 55?C a 100?C - erythritol: from 55?C to 100?C
- xilitolo: da 60?C a 100?C - xylitol: from 60?C to 100?C
- sorbitolo: da 65?C a 100?C - sorbitol: from 65?C to 100?C
Una volta solubilizzato, il polialcol rimane in soluzione anche quando la temperatura del solvente come l'alcol t-amilico diminuisce. A questo punto si pu? facilmente aggiungere l'acido carbossilico come l'ibuprofene per la sua solubilizzazione (da 100 di 300 mg a 5 mL di t-alcol amilico). Quindi, il solvente viene lasciato raffreddare per evitare la degradazione termica del catalizzatore enzimatico. Quando la temperatura del solvente ? di circa 65 ?C o inferiore, ? possibile caricare la quantit? predeterminata di enzima (intervallo da 10 a 55 mg in 5 mL di alcol t-amilico). Al solvente pu? essere aggiunto un certo numero di ?setacci molecolari? per eliminare l'acqua come sottoprodotto della formazione dell'estere legato (range da 50 a 100 mg in 5 mL di alcol t-amilico). Meno acqua nel sistema porta ad una pi? facile formazione dell'estere legato come mostrato nella reazione di equilibrio sopra riportata. Once solubilized, the polyalcohol remains in solution even when the temperature of the solvent such as t-amyl alcohol decreases. At this point you can? easily add carboxylic acid such as ibuprofen for its solubilization (100 of 300 mg to 5 mL of t-amyl alcohol). Then, the solvent is allowed to cool to avoid thermal degradation of the enzyme catalyst. When is the temperature of the solvent ? approximately 65 ?C or lower, ? is it possible to load the quantity? predetermined amount of enzyme (range 10 to 55 mg in 5 mL of t-amyl alcohol). Solvent can? be added a certain number of ?molecular sieves? to remove water as a byproduct of bound ester formation (range 50 to 100 mg in 5 mL of t-amyl alcohol). Less water in the system leads to more? easy formation of the bonded ester as shown in the equilibrium reaction above.
Il reattore pu? essere preferenzialmente posto in bagno di glicerina/olio di silicone posto sull'agitatore magnetico per mantenere costante la temperatura. Alcuni agitatori magnetici hanno un termometro che, se posto nel bagno di glicerina, pu? auto-impostare la forza di riscaldamento dell'agitatore in modo da mantenere costante nel tempo la temperatura desiderata. La velocit? di agitazione deve essere impostata da 100 a 200 RMP per evitare la distruzione meccanica del catalizzatore. Ad esempio, il rapporto molare acido: alcol pu? essere 5: 1. Dopo 24 ore, o anche meno, si forma estere che ? purificabile dalla reazione. The reactor can preferably be placed in a glycerine/silicone oil bath placed on the magnetic stirrer to keep the temperature constant. Some magnetic stirrers have a thermometer which, if placed in the glycerine bath, can auto-set the heating force of the stirrer in order to keep the desired temperature constant over time. The speed? stirring speed should be set from 100 to 200 RMP to avoid mechanical destruction of the catalyst. For example, the acid:alcohol molar ratio can be 5: 1. After 24 hours, or even less, ester is formed which ? purified by the reaction.
? importante notare che non tutti i solventi organici possono portare a questo tipo di processo di esterificazione. In effetti, la scelta del solvente giusto ? fondamentale. Sebbene diversi solventi siano stati usati nella sintesi enzimatica, nessuno ? adatto per il processo della presente invenzione. Molti solventi organici apolari (fino a logP 2) possono asportare lo strato d'acqua che permette la giusta conformazione enzimatica, provocandone la denaturazione. Molti solventi polari non possono solubilizzare l'acido carbossilico come l'ibuprofene. DMSO disattiva l'enzima. Alcuni solventi organici (come il metanolo) sono alcoli cos? piccoli che interagiscono con il sito attivo dell'enzima, inattivandolo. Altri alcol a catena lunga (ad esempio: ottanolo) possono prendere parte alla reazione come substrato. Inoltre, nessuno dei comuni solventi organici, che sono stati testati, pu? solubilizzare sia l'acido carbossilico come l'ibuprofene che il polialcol (log P da: 3,75 a -3,36). ? It is important to note that not all organic solvents can lead to this type of esterification process. Indeed, the choice of the right solvent ? basic. Although several solvents have been used in enzymatic synthesis, none are suitable for the process of the present invention. Many apolar organic solvents (up to logP 2) can remove the layer of water which allows for the right enzymatic conformation, causing its denaturation. Many polar solvents cannot solubilize carboxylic acid such as ibuprofen. DMSO deactivates the enzyme. Some organic solvents (such as methanol) are alcohols so? small ones that interact with the active site of the enzyme, inactivating it. Other long-chain alcohols (for example: octanol) can take part in the reaction as a substrate. Furthermore, none of the common organic solvents, which have been tested, can? solubilize both carboxylic acid such as ibuprofen and polyalcohol (log P: 3.75 to -3.36).
Secondo la presente invenzione, sono stati selezionati solventi adatti, come l'alcol t-amilico. Inoltre, come menzionato precedentemente, pu? essere richiesta una fase di solubilizzazione preliminare. According to the present invention, suitable solvents such as t-amyl alcohol have been selected. Also, as previously mentioned, it can a preliminary solubilization step may be required.
Forma pertanto oggetto specifico della presente invenzione un processo per la preparazione di un estere di un acido carbossilico con una molecola portatrice di un gruppo idrossilico, detto acido carbossilico essendo scarsamente solubile in acqua e la molecola portatrice di un gruppo idrossilico essendo un composto solido, in cui il processo comprende o consiste in: Therefore, a specific object of the present invention is a process for the preparation of an ester of a carboxylic acid with a molecule carrying a hydroxyl group, said carboxylic acid being sparingly soluble in water and the molecule carrying a hydroxyl group being a solid compound, in which the process includes or consists of:
a) solubilizzare l'acido carbossilico e la molecola portatrice di un gruppo idrossilico in una fase organica in grado di solubilizzare sia l'acido carbossilico sia la molecola portatrice di un gruppo idrossilico; e b) aggiungere un catalizzatore enzimatico adatto a catalizzare l'esterificazione, sotto agitazione; a) solubilizing the carboxylic acid and the molecule carrying a hydroxyl group in an organic phase capable of solubilizing both the carboxylic acid and the molecule carrying a hydroxyl group; and b) adding an enzymatic catalyst suitable for catalyzing the esterification, under stirring;
in cui detta una fase organica comprende o consiste in un alcol terziario o un nitrile terziario con un numero di atomi di carbonio da 4 a 10, preferibilmente da 4 a 8, pi? preferibilmente da 4 a 6, o loro miscele e detto catalizzatore enzimatico ? una idrolasi a serina in una forma cataliticamente attiva. wherein said an organic phase comprises or consists of a tertiary alcohol or a tertiary nitrile having a number of carbon atoms from 4 to 10, preferably from 4 to 8, plus? preferably from 4 to 6, or mixtures thereof, and said enzymatic catalyst ? a serine hydrolase in a catalytically active form.
Per "scarsamente idrosolubile" si intende un acido carbossilico in grado di essere solubilizzato dalla fase organica. In particolare, un acido carbossilico scarsamente solubile in acqua ? preferibilmente un acido carbossilico avente una solubilit? in acqua che rientra nell'intervallo di leggermente solubile e inferiore, cio? una solubilit? acquosa <10 mg/mL (questo intervallo comprende anche acidi carbossilici insolubili in acqua, cio? acidi carbossilici aventi una solubilit? acquosa <100 ?g / mL). L'acido carbossilico secondo la presente invenzione pu? avere una solubilit? acquosa da 100 ?g/mL a 10 mg/mL. By "poorly water soluble" is meant a carboxylic acid capable of being solubilized from the organic phase. In particular, a carboxylic acid which is poorly soluble in water ? preferably a carboxylic acid having a solubility? in water that falls within the range of slightly soluble and lower, cio? a solubility? <10 mg/mL (this range also includes water-insoluble carboxylic acids, i.e. carboxylic acids having an aqueous solubility <100 ?g/mL). The carboxylic acid according to the present invention can have a solubility? aqueous from 100 µg/mL to 10 mg/mL.
Secondo il processo della presente invenzione nella fase a) la molecola portatrice di un gruppo idrossile pu? essere solubilizzata in detta una fase organica sotto riscaldamento e agitazione prima di aggiungere l'acido carbossilico. According to the process of the present invention in step a) the molecule carrying a hydroxyl group can be solubilized in said one organic phase under heating and stirring before adding the carboxylic acid.
La temperatura di riscaldamento dipende dalla molecola portatrice di un gruppo idrossilico. Se viene utilizzato il riscaldamento, il catalizzatore enzimatico viene aggiunto quando la temperatura viene abbassata a una temperatura in cui l'enzima ? attivo. Ad esempio, quando l'enzima ? CALB, questo enzima ? attivo a una temperatura uguale o inferiore a 80?C. Preferibilmente, CALB pu? essere utilizzato a una temperatura inferiore a 70?C, pi? preferibilmente inferiore a 65?C. The heating temperature depends on the molecule carrying a hydroxyl group. If heating is used, the enzyme catalyst is added when the temperature is lowered to a temperature where the enzyme is released. active. For example, when the enzyme ? CALB, this enzyme? active at or below 80?C. Preferably, CALB can be used at a temperature lower than 70?C, pi? preferably lower than 65°C.
Secondo il processo della presente invenzione, il rapporto tra l'acido carbossilico e la molecola che trasporta il gruppo ossidrile pu? variare da 10:1 a 1:10, ad esempio da 5:1 a 1:5. According to the process of the present invention, the ratio of the carboxylic acid to the molecule carrying the hydroxyl group can be vary from 10:1 to 1:10, for example from 5:1 to 1:5.
Secondo una forma di realizzazione preferita, il rapporto tra l'acido carbossilico e la molecola portatrice di un gruppo idrossilico pu? variare da 10: 1 a 1: 1, ad esempio da 5: 1 a 1: 1, con esclusione del rapporto 1:1, cio? si preferisce un eccesso dell'acido carbossilico rispetto alla quantit? della molecola portatrice di un gruppo idrossile, ad esempio un rapporto di 5:1. According to a preferred embodiment, the ratio between the carboxylic acid and the molecule carrying a hydroxyl group can be vary from 10: 1 to 1: 1, for example from 5: 1 to 1: 1, with the exclusion of the ratio 1:1, the cio? you prefer an excess of the carboxylic acid with respect to the quantity? of the molecule carrying a hydroxyl group, for example a ratio of 5:1.
Secondo la presente invenzione, l'acido carbossilico pu? essere scelto dal gruppo consistente in ibuprofene, acido mandelico, acido ursodesossicolico, acido desossicolico, acido colico, acido sorbico, acido 3-fenilpropanoico, acido cinnamico, 3- (4-idrossifenil) propionico acido, acido 3,5-dimetossi-4-idrossicinnamico, acido benzoico, acido (2E) -3- (4-idrossifenil) prop-2-enoico (acido p-cumarico), acido 3,4,5-triidrossibenzoico (gallico acido), acido benzene-1,2-dicarbossilico (acido ftalico), acido 2-idrossibenzoico (acido salicilico), acido acetilsalicilico, acido succinico, acido stearico, acido tartarico, acido glutammico, acido malonico, (2E) -But-2 -acido endoico (acido fumarico) e indometacina. According to the present invention, the carboxylic acid can be selected from the group consisting of ibuprofen, mandelic acid, ursodeoxycholic acid, deoxycholic acid, cholic acid, sorbic acid, 3-phenylpropanoic acid, cinnamic acid, 3- (4-hydroxyphenyl) propionic acid, 3,5-dimethoxy-4- hydroxycinnamic, benzoic acid, (2E) -3- (4-hydroxyphenyl) prop-2-enoic acid (p-coumaric acid), 3,4,5-trihydroxybenzoic acid (gallic acid), benzene-1,2-dicarboxylic acid (phthalic acid), 2-hydroxybenzoic acid (salicylic acid), acetylsalicylic acid, succinic acid, stearic acid, tartaric acid, glutamic acid, malonic acid, (2E)-But-2 -endoic acid (fumaric acid), and indomethacin.
Secondo la presente invenzione, la molecola portatrice di un gruppo idrossilico pu? essere una molecola avente un valore LogP da -4,7 a 0,15, preferibilmente da -4,7 a 0, pi? preferibilmente da -3,36 a 0, e portante almeno due gruppi idrossilici, preferibilmente almeno tre gruppi idrossilici, pi? preferibilmente almeno quattro gruppi idrossilici, ancor pi? preferibilmente almeno cinque gruppi idrossilici o almeno sei gruppi idrossilici. According to the present invention, the molecule carrying a hydroxyl group can be a molecule having a LogP value of -4.7 to 0.15, preferably -4.7 to 0, more? preferably from -3.36 to 0, and carrying at least two hydroxyl groups, preferably at least three hydroxyl groups, plus? preferably at least four hydroxyl groups, even more? preferably at least five hydroxyl groups or at least six hydroxyl groups.
In particolare, detta molecola portatrice di un gruppo idrossilico pu? essere scelta dal gruppo consistente in un polialcol come sorbitolo, xilitolo, eritritolo, glicole etilenico, etene-1,1-diolo, (2E) -2-butene-1,4- diolo, maltitolo o isomalto, preferibilmente sorbitolo; uno zucchero come glucosio, fruttosio o saccarosio; o acido ascorbico. In particular, said molecule carrying a hydroxyl group can be selected from the group consisting of a polyalcohol such as sorbitol, xylitol, erythritol, ethylene glycol, ethene-1,1-diol, (2E)-2-butene-1,4-diol, maltitol or isomalt, preferably sorbitol; a sugar such as glucose, fructose, or sucrose; or ascorbic acid.
La tabella 1 di seguito mostra i valori LogP di alcune delle molecole portatrici di un gruppo idrossilico sopra menzionate. Table 1 below shows the LogP values of some of the above-mentioned molecules carrying a hydroxyl group.
Tabella 1 Table 1
Secondo la presente invenzione, detto alcol terziario pu? essere t-amil alcol o t-butanolo e detto nitrile terziario pu? essere trimetilacetonitrile. According to the present invention, said tertiary alcohol can be t-amyl alcohol or t-butanol and said tertiary nitrile can? be trimethylacetonitrile.
Secondo una forma di realizzazione della presente invenzione, detto catalizzatore enzimatico pu? essere un catalizzatore enzimatico immobilizzato. According to an embodiment of the present invention, said enzymatic catalyst can be an immobilized enzyme catalyst.
Secondo il processo della presente invenzione, detta serina idrolasi pu? essere scelta dal gruppo consistente in lipasi o serina proteasi, come subtilisina o tripsina. According to the process of the present invention, said serine hydrolase can be selected from the group consisting of lipase or serine protease, such as subtilisin or trypsin.
In particolare, detta lipasi pu? essere scelta dal gruppo consistente in C. antarctica lipasi B, lipasi da R. miehei, lipasi da T. lanuginosus o C. antarctica lipasi A, preferibilmente C. antarctica lipasi B, pi? preferibilmente una C. antarctica lipasi B immobilizzata. In particular, said lipase pu? be selected from the group consisting of C. antarctica lipase B, lipase from R. miehei, lipase from T. lanuginosus or C. antarctica lipase A, preferably C. antarctica lipase B, plus? preferably an immobilized C. antarctica lipase B.
CALB mostra una triade catalitica Ser-His-Asp nel suo sito attivo, con un coperchio (?lid?) molto piccolo che non ? in grado di isolare completamente il sito attivo. CALB shows a Ser-His-Asp catalytic triad in its active site, with a very small lid (?lid?) that is not ? capable of completely isolating the active site.
Esempi di lipasi disponibili in commercio che possono essere utilizzate secondo la presente invenzione sono Lipozyme? TL 100L (da Thermomyces lanuginosa), Lipozyme? CALB L (non immobilizzato, cio? libero, CALB), Lipozyme? CALA L e Novocor? AD L (non immobilizzata, cio? libera, lipasi A da Candida antarctica), Lipozyme? 435 (una lipasi ricombinante da Candida antarctica, espressa in Aspergillus niger e immobilizzata su Lewatit VP OC 1600).) Examples of commercially available lipases which can be used according to the present invention are Lipozyme? TL 100L (from Thermomyces lanuginosa), Lipozyme? CALB L (not immobilized, ie free, CALB), Lipozyme? CALA L and Novocor? AD L (not immobilized, ie free, lipase A from Candida antarctica), Lipozyme? 435 (a recombinant lipase from Candida antarctica, expressed in Aspergillus niger and immobilized on Lewatit VP OC 1600).)
Secondo una forma di realizzazione della presente invenzione, la fase a) e/o la fase b) possono comprendere l'aggiunta di uno o pi? setacci molecolari per rimuovere l'acqua dall'ambiente di reazione. Ad esempio, possono essere utilizzati i seguenti setacci molecolari: setacci molecolari, 4 ?, sfere, 4-8 mesh; setacci molecolari, 3 ?, sfere, 4-8 mesh; setacci molecolari, 3 ?, sfere, 8-12 mesh. According to an embodiment of the present invention, step a) and/or step b) can comprise the addition of one or more? molecular sieves to remove water from the reaction medium. For example, the following molecular sieves can be used: molecular sieves, 4?, spheres, 4-8 mesh; molecular sieves, 3?, spheres, 4-8 mesh; molecular sieves, 3 ?, spheres, 8-12 mesh.
Inoltre, la presente invenzione riguarda un estere di un acido carbossilico scarsamente solubile in acqua con una molecola portatrice di un gruppo idrossilico solida, in cui detto estere ? scelto dal gruppo consistente in: Furthermore, the present invention relates to an ester of a poorly water soluble carboxylic acid with a solid hydroxyl group carrier molecule, wherein said ester is? chosen from the group consisting of:
ibuprofene eritritolo estere, come 2,3,4-triidrossibutil 2- (4-isobutilfenil) propanoato, per esempio (2R, 3S) -2,3,4-triidrossibutil 2- (4-isobutilfenil) propanoato; ibuprofen erythritol ester, such as 2,3,4-trihydroxybutyl 2- (4-isobutylphenyl) propanoate, for example (2R, 3S) -2,3,4-trihydroxybutyl 2- (4-isobutylphenyl) propanoate;
ibuprofene xilitolo estere, come 2,3,4,5-tetraidrossipentil 2- (4-isobutilfenil) propanoato, ad esempio (2S, 3S, 4R) -2,3,4,5-tetraidrossipentil 2- (4-isobutilfenile) propanoato; ibuprofen xylitol ester, such as 2,3,4,5-tetrahydroxypentyl 2- (4-isobutylphenyl) propanoate, such as (2S, 3S, 4R) -2,3,4,5-tetrahydroxypentyl 2- (4-isobutylphenyl) propanoate ;
ibuprofene sorbitolo estere, come 2,3,4,5,6-pentaidrossesil 2- (4-isobutilfenil) propanoato, per esempio (2S, 3R, 4R, 5R) -2,3,4,5,6-pentaidrossesile 2 -(4-isobutilfenil) propanoato; ibuprofen sorbitol ester, such as 2,3,4,5,6-pentahydroxyl 2- (4-isobutylphenyl)propanoate, for example (2S, 3R, 4R, 5R) -2,3,4,5,6-pentahydroxyl 2 - (4-isobutylphenyl)propanoate;
estere dell'acido mandelico con acido ascorbico, come 2- (3,4-diidrossi-5-osso-2,5-diidrofuran-2-il) -2-idrossietil 2-idrossi-2-fenilacetato, ad esempio (S) -2 - ((R) -3,4-diidrossi-5-osso-2,5-diidrofuran -2-il) -2-idrossietil 2-idrossi-2-fenilacetato; ester of mandelic acid with ascorbic acid, such as 2- (3,4-dihydroxy-5-oxo-2,5-dihydrofuran-2-yl) -2-hydroxyethyl 2-hydroxy-2-phenylacetate, e.g. (S) -2 - ((R) -3,4-dihydroxy-5-oxo-2,5-dihydrofuran -2-yl) -2-hydroxyethyl 2-hydroxy-2-phenylacetate;
estere dell'eritritolo dell'acido ursodesossicolico, come 2,3,4-triidrossibutil 4- (3,7-diidrossi-10,13- dimetilesadecaidro-1H-ciclopenta [a] fenantrene-17-il) pentanoato, ad esempio (2S, 3R) -2,3,4-triidrossibutile (R) -4 - ((3R, 5S, 7S, 8R, 9S, 10S, 13R, 14S, 17R) -3,7-diidrossi-10,13-dimetilesadecaidro-1H-ciclopenta [a] fenantren-17-il) pentanoato; ursodeoxycholic acid erythritol ester, such as 2,3,4-trihydroxybutyl 4- (3,7-dihydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanoate, e.g. (2S , 3R) -2,3,4-trihydroxybutyl (R) -4 - ((3R, 5S, 7S, 8R, 9S, 10S, 13R, 14S, 17R) -3,7-dihydroxy-10,13-dimethylhexadecahydro- 1H-cyclopenta [a]phenanthrene-17-yl) pentanoate;
estere di xilitolo dell'acido ursodesossicolico, come 2,3,4,5-tetraidrossipentil 4- (3,7-diidrossi-10,13-dimetilesadecaidro-1H-ciclopenta [a] fenan-17-il) pentanoato, ad esempio (2S, 3S, 4R) -2,3,4,5-tetraidrossipentil (R) -4 - ((3R, 5S, 7S, 8R, 9S, 10S, 13R, 14S, 17R) -3,7-diidrossi-10,13 -dimetilesadecaidro-1H-ciclopenta [a] fenantren-17-il) pentanoato; ursodeoxycholic acid xylitol ester, such as 2,3,4,5-tetrahydroxypentyl 4-(3,7-dihydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenan-17-yl)pentanoate, e.g. ( 2S, 3S, 4R) -2,3,4,5-tetrahydroxypentyl (R) -4 - ((3R, 5S, 7S, 8R, 9S, 10S, 13R, 14S, 17R) -3,7-dihydroxy-10 ,13 -dimethylhexadecahydro-1H-cyclopenta [a]phenanthrene-17-yl) pentanoate;
ursodeoxycholic acid sorbitol ester, such as 2,3,4,5,6-pentahydroxyhexyl 4-(3,7-dihydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)pentanoate, for example (2R,3R,4R,5S)-2,3,4,5,6-pentahydroxyhexyl (R)-4-((3R,5S,7S,8R,9S,10S, 13R,14S,17R)-3,7-dihydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)pentanoate; ursodeoxycholic acid sorbitol ester, such as 2,3,4,5,6-pentahydroxyhexyl 4-(3,7-dihydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)pentanoate, for example ( 2R,3R,4R,5S)-2,3,4,5,6-pentahydroxyhexyl (R)-4-((3R,5S,7S,8R,9S,10S, 13R,14S,17R)-3,7 -dihydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)pentanoate;
estere dell'eritritolo dell'acido desossicolico, come 2,3,4-triidrossibutil 4- (3,12-diidrossi-10,13-dimetilesadecaidro-1H-ciclopenta [a] fenantren-17-il) pentanoato, ad esempio (2S, 3R) -2,3,4-triidrossibutil (R) -4 - ((3R, 5R, 8R, 9S, 10S, 12S, 13R, 14S, 17R) -3,12-diidrossi-10,13-dimetilesadecaidro-1H-ciclopenta [a] fenantren-17-il) pentanoato; deoxycholic acid erythritol ester, such as 2,3,4-trihydroxybutyl 4-(3,12-dihydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanoate, e.g. (2S , 3R) -2,3,4-trihydroxybutyl (R) -4 - ((3R, 5R, 8R, 9S, 10S, 12S, 13R, 14S, 17R) -3,12-dihydroxy-10,13-dimethylhexadecahydro- 1H-cyclopenta [a]phenanthrene-17-yl) pentanoate;
estere di xilitolo dell'acido desossicolico, come 2,3,4,5-tetraidrossipentil 4- (3,12-diidrossi-10,13-dimetilesadecaidro-1H-ciclopenta [a] fenantrene-17-il) pentanoato, ad esempio (2S, 3S, 4R) -2,3,4,5-tetraidrossipentil (R) -4 - ((3R, 5R, 8R, 9S, 10S, 12S, 13R, 14S, 17R) -3,12-diidrossi-10,13 -dimetilesadecaidro -1H-ciclopenta [a] fenantren-17-il) pentanoato; deoxycholic acid xylitol ester, such as 2,3,4,5-tetrahydroxypentyl 4-(3,12-dihydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanoate, e.g. ( 2S, 3S, 4R) -2,3,4,5-tetrahydroxypentyl (R) -4 - ((3R, 5R, 8R, 9S, 10S, 12S, 13R, 14S, 17R) -3,12-dihydroxy-10 ,13 -dimethylhexadecahydro -1H-cyclopenta [a]phenanthrene-17-yl) pentanoate;
estere di sorbitolo dell'acido desossicolico, come 2,3,4,5,6-pentaidrossesil 4- (3,12-diidrossi-10,13-dimetilesadecaidro-1H-ciclopenta [a] fenantrene-17-il) pentanoato, ad esempio ( 2R, 3R, 4R, 5S) -2,3,4,5,6-pentaidrossesil (R) -4 - ((3R, 5R, 8R, 9S, 10S, 12S, 13R, 14S, 17R) -3,12 -diidrossi-10,13-dimetilesadecaidro -1H-ciclopenta [a] fenan-17-il) pentanoato; deoxycholic acid sorbitol ester, such as 2,3,4,5,6-pentahydroxyl 4-(3,12-dihydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanoate, such as example ( 2R, 3R, 4R, 5S) -2,3,4,5,6-pentahydroxyl (R) -4 - ((3R, 5R, 8R, 9S, 10S, 12S, 13R, 14S, 17R) -3 ,12 -dihydroxy-10,13-dimethylhexadecahydro -1H-cyclopenta [a]phenan-17-yl) pentanoate;
estere dell'eritritolo dell'acido sorbico, come 2,3,4-triidrossibutil (2E, 4E) -esa-2,4-dienoato, per esempio (2S, 3R) -2,3,4-triidrossibutil (2E, 4E) -esa -2,4-dienoato; sorbic acid erythritol ester, such as 2,3,4-trihydroxybutyl (2E, 4E) -hexa-2,4-dienoate, e.g. (2S, 3R) -2,3,4-trihydroxybutyl (2E, 4E ) -hex -2,4-dienoate;
estere di xilitolo dell'acido sorbico, come 2,3,4,5-tetraidrossipentil (2E, 4E) -esa-2,4-dienoato, ad esempio (2S, 3S, 4R) -2,3,4,5-tetraidrossipentil ( 2E, 4E) -exa-2,4-dienoato; xylitol ester of sorbic acid, such as 2,3,4,5-tetrahydroxypentyl (2E, 4E) -hexa-2,4-dienoate, such as (2S, 3S, 4R) -2,3,4,5- tetrahydroxypentyl (2E,4E)-hexa-2,4-dienoate;
estere di sorbitolo dell'acido sorbico, come 2,3,4,5,6-pentaidrossesil (2E, 4E) -esa-2,4-dienoato, ad esempio (2R, 3R, 4R, 5S) -2,3,4, 5,6-pentaidrossesil (2E, 4E) -esa-2,4-dienoato; sorbitol ester of sorbic acid, such as 2,3,4,5,6-pentahydroxyl (2E, 4E) -hexa-2,4-dienoate, such as (2R, 3R, 4R, 5S) -2,3, 4, 5,6-pentahydroxyl (2E, 4E) -hexa-2,4-dienoate;
estere dell'eritritolo dell'acido 3-fenilpropanoico, come 2,3,4-triidrossibutil 3-fenilpropanoato, per esempio (2S, 3R) -2,3,4-triidrossibutil 3-fenilpropanoato; 3-phenylpropanoic acid erythritol ester, such as 2,3,4-trihydroxybutyl 3-phenylpropanoate, e.g. (2S,3R)-2,3,4-trihydroxybutyl 3-phenylpropanoate;
estere dell'acido 3-fenilpropanoico con xilitolo, come 2,3,4,5-tetraidrossipentil 3-fenilpropanoato, per esempio (2S, 3S, 4R) -2,3,4,5-tetraidrossipentil 3-fenilpropanoato; 3-phenylpropanoic acid ester with xylitol, such as 2,3,4,5-tetrahydroxypentyl 3-phenylpropanoate, e.g. (2S,3S,4R)-2,3,4,5-tetrahydroxypentyl 3-phenylpropanoate;
Estere con sorbitolo dell'acido 3-fenilpropanoico, come 2,3,4,5,6-pentaidrossesil 3-fenilpropanoato, ad esempio (2R, 3R, 4R, 5S) -2,3,4,5,6-pentaidrossesil 3-fenilpropanoato ; Sorbitol ester of 3-phenylpropanoic acid, such as 2,3,4,5,6-pentahydroxyl 3-phenylpropanoate, e.g. (2R, 3R, 4R, 5S) -2,3,4,5,6-pentahydroxyl 3 -phenylpropanoate;
estere con eritritolo dell'acido 3- (4-idrossifenil) propionico, come 2,3,4-triidrossibutil 3- (4-idrossifenil) propanoato, ad esempio (2S, 3R) -2,3,4-triidrossibutil 3- (4- idrossifenil) propanoato; erythritol ester of 3- (4-hydroxyphenyl) propionic acid, such as 2,3,4-trihydroxybutyl 3- (4-hydroxyphenyl) propanoate, e.g. (2S, 3R) -2,3,4-trihydroxybutyl 3- ( 4-hydroxyphenyl)propanoate;
estere dell'acido 3- (4-idrossifenil) propionico xilitolo, come 2,3,4,5-tetraidrossipentil 3- (4-idrossifenil) propanoato, ad esempio (2S, 3S, 4R) -2,3,4,5- 3- (4-idrossifenil) propanoato di tetraidrossipentil; 3- (4-Hydroxyphenyl)propionic acid xylitol ester, such as 2,3,4,5-Tetrahydroxypentyl 3- (4-Hydroxyphenyl)propanoate, e.g. (2S, 3S, 4R)-2,3,4,5 - Tetrahydroxypentyl 3- (4-hydroxyphenyl) propanoate;
estere con sorbitolo dell'acido 3- (4-idrossifenil) propionico, come (2,3,4,5,6-pentaidrossesil 3- (4-idrossifenil) propanoato, ad esempio (2R, 3R, 4R, 5S) -2,3 , 4,5,6-pentaidrossesil 3- (4-idrossifenil) propanoato; sorbitol ester of 3- (4-hydroxyphenyl) propionic acid, such as (2,3,4,5,6-pentahydroxyphenyl 3- (4-hydroxyphenyl) propanoate, e.g. (2R, 3R, 4R, 5S) -2 ,3,4,5,6-pentahydroxyl 3- (4-hydroxyphenyl) propanoate;
estere con eritritolo dell'acido 3,5-dimetossi-4-idrossicinnamico, come 2,3,4-triidrossibutil (E) -3- (4-idrossi-3,5-dimetossifenil) acrilato, ad esempio (2S, 3R) -2, 3,4-triidrossibutil (E) -3- (4-idrossi-3,5-dimetossifenil) acrilato; erythritol ester of 3,5-dimethoxy-4-hydroxycinnamic acid, such as 2,3,4-trihydroxybutyl (E) -3- (4-hydroxy-3,5-dimethoxyphenyl) acrylate, e.g. (2S, 3R) -2,3,4-trihydroxybutyl (E) -3- (4-hydroxy-3,5-dimethoxyphenyl) acrylate;
estere con xilitolo dell'acido 3,5-dimetossi-4-idrossicinnamico, come 2,3,4,5-tetraidrossipentil (E) -3- (4-idrossi-3,5-dimetossifenil) acrilato, ad esempio (2S, 3S, 4R) -2,3,4,5-tetraidrossipentil (E) -3- (4-idrossi-3,5-dimetossifenil) acrilato; 3,5-dimethoxy-4-hydroxycinnamic acid xylitol ester, such as 2,3,4,5-tetrahydroxypentyl (E) -3- (4-hydroxy-3,5-dimethoxyphenyl) acrylate, e.g. (2S, 3S, 4R) -2,3,4,5-tetrahydroxypentyl (E) -3- (4-hydroxy-3,5-dimethoxyphenyl) acrylate;
estere con sorbitolo dell'acido 3,5-dimetossi-4-idrossicinnamico, come 2,3,4,5,6-pentaidrossesil (E) -3(4-idrossi-3,5-dimetossifenil) acrilato, ad esempio (2R, 3R, 4R, 5S) -2,3,4,5,6-pentaidrossesil (E) -3- (4-idrossi-3,5-dimetossifenil) acrilato. sorbitol ester of 3,5-dimethoxy-4-hydroxycinnamic acid, such as 2,3,4,5,6-pentahydroxyl (E) -3(4-hydroxy-3,5-dimethoxyphenyl) acrylate, e.g. (2R , 3R, 4R, 5S) -2,3,4,5,6-pentahydroxyphenyl (E) -3- (4-hydroxy-3,5-dimethoxyphenyl) acrylate.
La presente invenzione riguarda anche una composizione farmaceutica comprendente o consistente in un estere come definito sopra in combinazione con uno o pi? eccipienti e/o adiuvanti. The present invention also relates to a pharmaceutical composition comprising or consisting of an ester as defined above in combination with one or more? excipients and/or adjuvants.
Un ulteriore oggetto della presente invenzione ? un estere come definito sopra o una composizione farmaceutica come definita sopra per l'uso nella terapia antinfiammatoria quando l'acido carbossilico ? ibuprofene. A further object of the present invention ? an ester as defined above or a pharmaceutical composition as defined above for use in anti-inflammatory therapy when the carboxylic acid is ibuprofen.
Un ulteriore oggetto della presente invenzione ? un estere come definito sopra o una composizione farmaceutica come definita sopra per l'uso nel trattamento dei calcoli biliari quando l'acido carbossilico ? acido ursodesossicolico o acido desossicolico. A further object of the present invention ? an ester as defined above or a pharmaceutical composition as defined above for use in the treatment of gallstones when the carboxylic acid is ursodeoxycholic acid or deoxycholic acid.
Tra gli esteri della presente invenzione: Among the esters of the present invention:
- gli esteri dell'acido sorbico possono essere usati come agenti antimicrobici, come conservanti alimentari; - sorbic acid esters can be used as antimicrobial agents, as food preservatives;
- gli esteri dell'acido mandelico possono essere utilizzati nei cosmetici, ad esempio possono essere utilizzati come agenti antiet?; - mandelic acid esters can be used in cosmetics, for example they can be used as anti-aging agents;
- esteri di acidi aromatici come l'acido 3-fenilpropanoico o l'acido 3- (4-idrossifenil) propionico possono essere utilizzati nei cosmetici, come additivi alimentari o nei prodotti farmaceutici; - esters of aromatic acids such as 3-phenylpropanoic acid or 3- (4-hydroxyphenyl) propionic acid can be used in cosmetics, as food additives or in pharmaceuticals;
- gli esteri dell'acido 3,5-dimetossi-4-idrossicinnamico possono essere utilizzati in matrice per tecniche spettrofotometriche, come la spettrometria di massa MALDI; - 3,5-dimethoxy-4-hydroxycinnamic acid esters can be used in matrix for spectrophotometric techniques, such as MALDI mass spectrometry;
- gli esteri dell'indometacina possono essere usati come farmaci antinfiammatori non steroidei; - indomethacin esters can be used as non-steroidal anti-inflammatory drugs;
- gli esteri dell'acido fumarico possono essere utilizzati nell'industria farmaceutica e / o alimentare; - fumaric acid esters can be used in the pharmaceutical and/or food industry;
- gli esteri dell'acido malonico possono essere utilizzati per la preparazione di aromi e fragranze; - malonic acid esters can be used for the preparation of flavors and fragrances;
- gli esteri dell'acido glutammico possono essere utilizzati come additivi alimentari; - glutamic acid esters can be used as food additives;
- gli esteri dell'acido tartarico possono essere utilizzati come agenti antiossidanti; - tartaric acid esters can be used as antioxidant agents;
- gli esteri dell'acido stearico possono essere utilizzati come tensioattivi; - stearic acid esters can be used as surfactants;
- gli esteri dell'acido succinico possono essere utilizzati nell'industria alimentare, ad esempio come regolatori di acidit? e agenti aromatizzanti; - can succinic acid esters be used in the food industry, for example as acidity regulators? and flavoring agents;
- gli esteri degli acidi salicilici o acetilsalicilici possono essere utilizzati come agenti antinfiammatori; - esters of salicylic or acetylsalicylic acids can be used as anti-inflammatory agents;
- gli esteri dell'acido ftalico possono essere usati come plastificanti; - phthalic acid esters can be used as plasticizers;
- gli esteri dell'acido gallico o dell'acido pcumarico possono essere utilizzati come agenti antiossidanti. - esters of gallic acid or pcumaric acid can be used as antioxidant agents.
Sulla base di quanto sopra, il processo della presente invenzione pu? essere utilizzato sia per la produzione di molecole note che per la sintesi di nuovi derivati, come i tre esteri dell'ibuprofene mostrati in Figura 1. Queste tre molecole, oggetto di brevetto sono potenziali candidati alla sperimentazione in vivo e in vitro come nuovi agenti antinfiammatori con una migliore biodisponibilit? al posto dell'ibuprofene. Come accennato in precedenza, il sorbitolo ? un polialcol che pu? essere utilizzato come potenziatore dell'idrofilia. Sorbitolo ((2R, 3R, 4R, 5S) -esano-1,2,3,4,5,6-esolo), meno comunemente noto come glucitolo. Based on the above, the process of the present invention can be used both for the production of known molecules and for the synthesis of new derivatives, such as the three ibuprofen esters shown in Figure 1. These three molecules, subject to patent, are potential candidates for in vivo and in vitro experimentation as new anti-inflammatory agents with better bioavailability? instead of ibuprofen. As mentioned above, sorbitol is a polyalcohol that can? be used as a hydrophilicity enhancer. Sorbitol ((2R, 3R, 4R, 5S) -hexane-1,2,3,4,5,6-hexol), less commonly known as glucitol.
Il protocollo di sintesi sviluppato pu? essere utilizzato per sintesi ?verdi?, economiche e su scala semplice, per la produzione di esteri farmaceutici altamente puri e selettivi. Le tre sostanze chimiche, sintetizzate con il protocollo in oggetto, possono trovare applicazione come nuovi farmaci antinfiammatori non steroidei per il trattamento del dolore (cefalea, dismenorrea, dolore dentale) fino a disturbi muscoloscheletrici come l'osteoartrosi e l'artrite reumatoide. Questa tecnica pu? essere sfruttata da diversi settori, da quello farmaceutico a quello alimentare. Questo metodo pu? facilmente ottenere profarmaci, conservanti o esteri aromatici aumentati di solubilit?. The developed synthesis protocol can be used for low-cost, simple-scale "green" syntheses for the production of highly pure and selective pharmaceutical esters. The three chemical substances, synthesized with the protocol in question, can find application as new non-steroidal anti-inflammatory drugs for the treatment of pain (headache, dysmenorrhea, dental pain) up to musculoskeletal disorders such as osteoarthritis and rheumatoid arthritis. This technique can be exploited by various sectors, from the pharmaceutical to the food sector. This method can easily obtain prodrugs, preservatives or aromatic esters increased in solubility.
La presente invenzione verr? ora descritta in modo illustrativo, ma non limitativo, secondo sue forme di realizzazione preferite, con particolare riferimento agli esempi e ai disegni allegati, in cui: This invention will come now described in an illustrative, but non-limiting manner, according to preferred embodiments thereof, with particular reference to the examples and accompanying drawings, in which:
- la figura 1 mostra uno schema di formazione dell'estere catalizzato dalla lipasi legato tra ibuprofene e 3 differenti polialcolci solidi: a) estere ibuprofene eritritolo; b) ibuprofene xilitolo estere; c) ibuprofene sorbitolo estere; - figure 1 shows a scheme of formation of the ester catalysed by the lipase linked between ibuprofen and 3 different solid polyalcohols: a) ibuprofen erythritol ester; b) ibuprofen xylitol ester; c) ibuprofen sorbitol ester;
- la figura 2 mostra uno schema di reazione di esterificazione tra ibuprofene e acido ascorbico; - figure 2 shows an esterification reaction scheme between ibuprofen and ascorbic acid;
- la figura 3 mostra uno schema di esterificazione dell'acido mandelico con acido ascorbico; - figure 3 shows an esterification scheme of mandelic acid with ascorbic acid;
- La figura 4 mostra uno schema di formazione dell'estere catalizzato dalla lipasi legato tra acido ursodesossicolico (UDCA) e 3 differenti polialcolci solidi: a) UDCA eritritolo estere; b) UDCA xilitolo estere; c) UDCA sorbitolo estere; - Figure 4 shows a scheme of formation of the ester catalyzed by the lipase linked between ursodeoxycholic acid (UDCA) and 3 different solid polyalcohols: a) UDCA erythritol ester; b) UDCA xylitol ester; c) UDCA sorbitol ester;
- La figura 5 mostra uno schema di formazione dell'estere catalizzato dalla lipasi legato tra acido desossicolico (DCA) e 3 differenti polialcolci solidi: a) DCA eritritolo estere; b) DCA xilitolo estere; c) DCA sorbitolo estere; - Figure 5 shows a scheme of formation of the ester catalyzed by the lipase linked between deoxycholic acid (DCA) and 3 different solid polyalcohols: a) DCA erythritol ester; b) DCA xylitol ester; c) DCA sorbitol ester;
- la figura 6 mostra uno schema di formazione dell'estere catalizzato dalla lipasi legato tra acido sorbico e 3 differenti polialcolci solidi: a) estere eritritolo dell'acido sorbico; b) estere di xilitolo dell'acido sorbico; c) estere di sorbitolo dell'acido sorbico; - figure 6 shows a scheme of formation of the ester catalyzed by the lipase bound between sorbic acid and 3 different solid polyalcohols: a) erythritol ester of sorbic acid; b) xylitol ester of sorbic acid; c) sorbitol ester of sorbic acid;
- la figura 7 mostra uno schema di formazione dell'estere catalizzato da lipasi legato tra acido 3-fenilpropanoico e 3 differenti polialcolci solidi: a) estere eritritolico dell'acido 3-fenilpropanoico; b) estere xilitolo dell'acido 3-fenilpropanoico; c) estere di sorbitolo dell'acido 3-fenilpropanoico; - figure 7 shows a scheme of formation of the ester catalyzed by lipase linked between 3-phenylpropanoic acid and 3 different solid polyalcohols: a) erythritol ester of 3-phenylpropanoic acid; b) xylitol ester of 3-phenylpropanoic acid; c) sorbitol ester of 3-phenylpropanoic acid;
- la figura 8 mostra la reazione tra acido 3- (4-idrossifenil) propionico con 3 polialcol (eritritolo, xilitolo e sorbitolo); - figure 8 shows the reaction between 3-(4-hydroxyphenyl) propionic acid with 3 polyalcohols (erythritol, xylitol and sorbitol);
- la figura 9 mostra la reazione tra acido 3,5-dimetossi-4-idrossicinnamico con 3 polialcol (eritritolo, xilitolo e sorbitolo); - figure 9 shows the reaction between 3,5-dimethoxy-4-hydroxycinnamic acid with 3 polyalcohols (erythritol, xylitol and sorbitol);
- La figura 10 mostra la reazione tra acido benzoico con 3 polialcol (eritritolo, xilitolo e sorbitolo). - Figure 10 shows the reaction between benzoic acid with 3 polyalcohols (erythritol, xylitol and sorbitol).
ESEMPIO 1: Processo secondo la presente invenzione per la preparazione di esteri di ibuprofene. EXAMPLE 1: Process according to the present invention for the preparation of ibuprofen esters.
Uno schema di formazione dell'estere catalizzato dalla lipasi legato tra ibuprofene e 3 diversi polialcolci solidi ? mostrato in figura 1: a) estere di ibuprofene con eritritolo b) estere di ibuprofene con xilitolo c) estere di ibuprofene con sorbitolo. A pattern of lipase catalyzed ester formation bonded between ibuprofen and 3 different solid sugar alcohols? shown in figure 1: a) ibuprofen ester with erythritol b) ibuprofen ester with xylitol c) ibuprofen ester with sorbitol.
Sono stati testati i seguenti intervalli: The following ranges were tested:
- volumi di reazione: da 3 a 10 mL di alcol t-amilico - concentrazione enzimatica: da 5 a 18 gL-1 - reaction volumes: 3 to 10 mL of t-amyl alcohol - enzymatic concentration: 5 to 18 gL-1
- concentrazione dei setacci molecolari: da 10 a 32 gL-1 - velocit? di agitazione: da 150 a 220 RPM - concentration of molecular sieves: from 10 to 32 gL-1 - speed? stirring speed: from 150 to 220 RPM
a) Estere di ibuprofene con eritritolo: (2R, 3S) -2,3,4-triidrossibutil 2- (4-isobutilfenil) propanoato a) Ibuprofen erythritol ester: (2R, 3S) -2,3,4-trihydroxybutyl 2- (4-isobutylphenyl) propanoate
b) ibuprofene xilitolo estere: (2S, 3S, 4R) -2,3,4,5-tetraidrossipentil 2- (4-isobutilfenil) propanoato b) ibuprofen xylitol ester: (2S, 3S, 4R) -2,3,4,5-tetrahydroxypentyl 2- (4-isobutylphenyl) propanoate
c) Ibuprofene sorbitolo estere: (2S, 3R, 4R, 5R) -2,3,4,5,6-pentaidrossesil 2- (4-isobutilfenil) propanoato c) Ibuprofen sorbitol ester: (2S, 3R, 4R, 5R) -2,3,4,5,6-pentahydroxyl 2- (4-isobutylphenyl) propanoate
Uno schema di reazione di esterificazione tra ibuprofene e acido ascorbico ? mostrato in figura 2. An esterification reaction scheme between ibuprofen and ascorbic acid? shown in figure 2.
Ad esempio, (S) -2 - ((R) -3,4-diidrossi-5-osso-2,5-diidrofuran-2-il) -2-idrossietil 2- (4-isobutilfenil) propanoato ? ottenuto nel seguenti condizioni: For example, (S) -2 - ((R) -3,4-dihydroxy-5-oxo-2,5-dihydrofuran-2-yl) -2-hydroxyethyl 2- (4-isobutylphenyl) propanoate ? obtained under the following conditions:
ESEMPIO 2: Processo secondo la presente invenzione per la preparazione dell'estere dell'acido mandelico. EXAMPLE 2: Process according to the present invention for the preparation of the mandelic acid ester.
L'esterificazione dell'acido mandelico con acido ascorbico ? mostrata in figura 3. In particolare, (S) -2 - ((R) -3,4-diidrossi-5-osso-2,5-diidrofuran-2-il) -2-idrossietile Il 2-idrossi-2-fenilacetato si ottiene alle seguenti condizioni: The esterification of mandelic acid with ascorbic acid? shown in Fig. 3. In particular, (S) -2 - ((R) -3,4-dihydroxy-5-oxo-2,5-dihydrofuran-2-yl) -2-hydroxyethyl Il 2-hydroxy-2- Phenylacetate is obtained under the following conditions:
ESEMPIO 3: Processo secondo la presente invenzione per la preparazione di esteri di UDCA EXAMPLE 3: Process according to the present invention for the preparation of UDCA esters
Uno schema di formazione dell'estere catalizzato dalla lipasi legato tra acido ursodesossicolico (UDCA) e 3 differenti polialcolci solidi ? mostrato in figura 5: a) estere eritritolico UDCA; b) UDCA xilitolo estere; c) UDCA sorbitolo estere. A pattern of lipase catalyzed ester formation bonded between ursodeoxycholic acid (UDCA) and 3 different solid polyalcohols? shown in figure 5 : a) erythritol ester UDCA; b) UDCA xylitol ester; c) UDCA sorbitol ester.
a) Estere di UDCA con eritritolo: (2S, 3R) -2,3,4-triidrossibutil (R) -4 - ((3R, 5S, 7S, 8R, 9S, 10S, 13R, 14S, 17R) -3,7- diidrossi-10,13-dimetilesadecaidro-1 H-ciclopenta [a] fenan-17-il) pentanoato. a) UDCA ester with erythritol: (2S, 3R) -2,3,4-trihydroxybutyl (R) -4 - ((3R, 5S, 7S, 8R, 9S, 10S, 13R, 14S, 17R) -3, 7-Dihydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenan-17-yl)pentanoate.
La concentrazione di eritritolo ? limitata a 20 mg per portare la solubilizzazione di una quantit? 5 mol maggiore di UDCA in alcol t-amilico. The concentration of erythritol ? limited to 20 mg to bring the solubilization of a quantity? 5 mol greater of UDCA in t-amyl alcohol.
La stessa esterificazione pu? essere ottenuta con altri polialcol secondo le modalit? sopra descritte al fine di ottenere: The same esterification pu? be obtained with other polyalcohols according to the modalities? described above in order to obtain:
b) UDCA xilitolo estere: (2S, 3S, 4R) -2,3,4,5-tetraidrossipentil (R) -4 - ((3R, 5S, 7S, 8R, 9S, 10S, 13R, 14S, 17R) - 3,7-diidrossi-10,13-dimetilesadecaidro-1H ciclopenta [a] fenantren-17-il) pentanoato e b) UDCA xylitol ester: (2S, 3S, 4R) -2,3,4,5-tetrahydroxypentyl (R) -4 - ((3R, 5S, 7S, 8R, 9S, 10S, 13R, 14S, 17R) - 3,7-dihydroxy-10,13-dimethylhexadecahydro-1H cyclopenta [a]phenanthrene-17-yl) pentanoate and
c) UDCA sorbitolo estere: (2R, 3R, 4R, 5S) -2,3,4,5,6-pentaidrossesil (R) -4 - ((3R, 5S, 7S, 8R, 9S, 10S, 13R, 14S , 17R) -3,7-diidrossi-10,13-dimetilesadecaidro-1H ciclopenta [a] fenantren-17-il) pentanoato. c) UDCA sorbitol ester: (2R, 3R, 4R, 5S) -2,3,4,5,6-pentahydroxyl (R) -4 - ((3R, 5S, 7S, 8R, 9S, 10S, 13R, 14S , 17R)-3,7-dihydroxy-10,13-dimethylhexadecahydro-1H cyclopenta[a]phenanthrene-17-yl)pentanoate.
ESEMPIO 4: Processo secondo la presente invenzione per la preparazione di esteri DCA EXAMPLE 4: Process according to the present invention for the preparation of DCA esters
La figura 5 mostra uno schema di formazione dell'estere catalizzato dalla lipasi legato tra l'acido desossicolico (DCA) e 3 diversi polialcolci solidi: Figure 5 shows a pattern of lipase catalyzed ester formation bonded between deoxycholic acid (DCA) and 3 different solid polyalcohols:
a) estere dell'eritritolo DCA: a) erythritol ester DCA:
(2S, 3R) -2,3,4-triidrossibutil (R) -4 - ((3R, 5R, 8R, 9S, 10S, 12S, 13R, 14S, 17R) -3,12-diidrossi-10,13-dimetilesadecaidro-1Hciclopenta [a] fenantrene-17-il) pentanoato; (2S, 3R) -2,3,4-trihydroxybutyl (R) -4 - ((3R, 5R, 8R, 9S, 10S, 12S, 13R, 14S, 17R) -3,12-dihydroxy-10,13- dimethylhexadecahydro-1Hcyclopenta[a]phenanthrene-17-yl) pentanoate;
b) DCA xilitolo estere: b) DCA xylitol ester:
(2S, 3S, 4R) -2,3,4,5-tetraidrossipentil (R) -4 - ((3R, 5R, 8R, 9S, 10S, 12S, 13R, 14S, 17R) -3,12-diidrossi-10,13-dimetilesadecaidro-1Hciclopenta [a] fenantren-17-il) pentanoato; (2S, 3S, 4R) -2,3,4,5-tetrahydroxypentyl (R) -4 - ((3R, 5R, 8R, 9S, 10S, 12S, 13R, 14S, 17R) -3,12-dihydroxy- 10,13-dimethylhexadecahydro-1Hcyclopenta [a]phenanthrene-17-yl) pentanoate;
c) DCA sorbitolo estere: c) DCA sorbitol ester:
(2R, 3R, 4R, 5S) -2,3,4,5,6-pentaidrossesil (R) -4 -((3R, 5R, 8R, 9S, 10S, 12S, 13R, 14S, 17R) -3, 12-diidrossi-10,13-dimetilesadecaidro-1Hciclopenta [a] fenantren-17-il) pentanoato. (2R, 3R, 4R, 5S) -2,3,4,5,6-pentahydroxyl (R) -4 -((3R, 5R, 8R, 9S, 10S, 12S, 13R, 14S, 17R) -3, 12-Dihydroxy-10,13-dimethylhexadecahydro-1Hcyclopenta [a]phenanthrene-17-yl) pentanoate.
Gli esteri di DCA possono essere sintetizzati in modo analogo al metodo descritto della presente invenzione considerando il suo peso molecolare di 392,6 g/mol. DCA esters can be synthesized analogously to the described method of the present invention considering its molecular weight of 392.6 g/mol.
ESEMPIO 5: Processo secondo la presente invenzione per la preparazione di esteri dell'acido sorbico EXAMPLE 5: Process according to the present invention for the preparation of sorbic acid esters
Uno schema di formazione dell'estere catalizzato dalla lipasi legato tra acido sorbico e 3 differenti polialcol solidi ? mostrato in figura 6: a) estere dell'acido sorbico con eritritolo; b) estere di xilitolo dell'acido sorbico; c) estere di sorbitolo dell'acido sorbico. A pattern of lipase catalyzed ester formation bonded between sorbic acid and 3 different solid polyalcohols? shown in figure 6: a) ester of sorbic acid with erythritol; b) xylitol ester of sorbic acid; c) sorbitol ester of sorbic acid.
a) sorbic acid erythritol ester: a) sorbic acid erythritol ester:
(2S,3R)-2,3,4-trihydroxybutyl (2E,4E)-hexa-2,4-dienoate (2S,3R)-2,3,4-trihydroxybutyl (2E,4E)-hexa-2,4-dienoate
b) estere dell'acido sorbico con xilitolo: b) ester of sorbic acid with xylitol:
(2S, 3S, 4R) -2,3,4,5-tetraidrossipentile (2E, 4E) -esa-2,4-dienoato (2S, 3S, 4R) -2,3,4,5-tetrahydroxypentyl (2E, 4E) -hexa-2,4-dienoate
c) estere di sorbitolo dell'acido sorbico: c) sorbitol ester of sorbic acid:
(2R, 3R, 4R, 5S) -2,3,4,5,6-pentaidrossesile (2E, 4E) -exa-2,4-dienoato (2R, 3R, 4R, 5S) -2,3,4,5,6-pentahydroxyl (2E, 4E) -hexa-2,4-dienoate
ESEMPIO 6: Processo secondo la presente invenzione per la preparazione di esteri di acidi cinnamici EXAMPLE 6: Process according to the present invention for the preparation of cinnamic acid esters
La figura 7 mostra uno schema di formazione dell'estere catalizzato dalla lipasi legato tra l'acido 3-fenilpropanoico e 3 diversi polialcolci solidi: Figure 7 shows a pattern of bonded lipase catalyzed ester formation between 3-phenylpropanoic acid and 3 different solid polyalcohols:
a) estere dell'acido 3-fenilpropanoico con eritritolo: (2S, 3R) -2,3,4-triidrossibutil 3-fenilpropanoato; b) estere dell'acido 3-fenilpropanoico con xilitolo: (2S, 3S, 4R) -2,3,4,5-tetraidrossipentil 3-fenilpropanoato; a) 3-phenylpropanoic acid ester with erythritol: (2S, 3R) -2,3,4-trihydroxybutyl 3-phenylpropanoate; b) 3-phenylpropanoic acid ester with xylitol: (2S, 3S, 4R) -2,3,4,5-tetrahydroxypentyl 3-phenylpropanoate;
c) estere dell'acido 3-fenilpropanoico con sorbitolo: (2R, 3R, 4R, 5S) -2,3,4,5,6-pentaidrossesil 3-fenilpropanoato. c) 3-phenylpropanoic acid ester with sorbitol: (2R, 3R, 4R, 5S) -2,3,4,5,6-pentahydroxyl 3-phenylpropanoate.
Anche le seguenti forme di acido cinnamico sono esterificabili con il metodo dell'invenzione. The following forms of cinnamic acid are also esterifiable with the method of the invention.
La figura 8 mostra uno schema di formazione dell'estere catalizzato dalla lipasi legato tra acido 3(4-idrossifenil) propionico - (acido floretico) e 3 diversi polialcol solidi: Figure 8 shows a pattern of lipase catalyzed ester formation bonded between 3(4-hydroxyphenyl) propionic acid - (floretic acid) and 3 different solid polyalcohols:
a) Estere eritritolo dell'acido 3- (4-idrossifenil) propionico: (2S, 3R) -2,3,4-triidrossibutil 3- (4-idrossifenil) propanoato; a) 3- (4-hydroxyphenyl) propionic acid erythritol ester: (2S, 3R) -2,3,4-trihydroxybutyl 3- (4-hydroxyphenyl) propanoate;
b) 3-(4-Hydroxyphenyl)propionic acid xylitol ester: (2S,3S,4R)-2,3,4,5-tetrahydroxypentyl 3-(4-phydroxyphenyl)propanoate; b) 3-(4-Hydroxyphenyl)propionic acid xylitol ester: (2S,3S,4R)-2,3,4,5-tetrahydroxypentyl 3-(4-phydroxyphenyl)propanoate;
c) 3-(4-Hydroxyphenyl)propionic acid sorbitol ester: (2R,3R,4R,5S)-2,3,4,5,6-pentahydroxyhexyl 3-(4-hydroxyphenyl)propanoate; c) 3-(4-Hydroxyphenyl)propionic acid sorbitol ester: (2R,3R,4R,5S)-2,3,4,5,6-pentahydroxyhexyl 3-(4-hydroxyphenyl)propanoate;
e uno schema di formazione dell'estere catalizzato dalla lipasi legato tra la reazione dell'acido 3,5-dimetossi-4-idrossicinnamico - acido sinaptico e 3 diversi polialcol solidi ? mostrato in figura 9: and a lipase catalyzed ester formation pattern linked between the reaction of 3,5-dimethoxy-4-hydroxycinnamic acid - synaptic acid and 3 different solid polyalcohols ? shown in figure 9:
a) estere dell'eritritolo dell'acido 3,5-dimetossi-4-idrossicinnamico: (2S, 3R) -2,3,4-triidrossibutil (E) -3- (4-idrossi-3,5-dimetossifenil) acrilato; a) 3,5-dimethoxy-4-hydroxycinnamic acid erythritol ester: (2S, 3R) -2,3,4-trihydroxybutyl (E) -3- (4-hydroxy-3,5-dimethoxyphenyl) acrylate ;
b) estere dello xilitolo dell'acido 3,5-dimetossi-4-idrossicinnamico: (2S, 3S, 4R) -2,3,4,5-tetraidrossipentil (E) -3- (4-idrossi-3,5-dimetossifenil) acrilato ; b) 3,5-dimethoxy-4-hydroxycinnamic acid xylitol ester: (2S, 3S, 4R) -2,3,4,5-tetrahydroxypentyl (E) -3- (4-hydroxy-3,5- dimethoxyphenyl) acrylate;
c) estere del sorbitolo dell'acido 3,5-dimetossi-4-idrossicinnamico: (2R, 3R, 4R, 5S) -2,3,4,5,6-pentaidrossesil (E) -3- (4-idrossi-3,5 -dimetossifenil) acrilato c) 3,5-dimethoxy-4-hydroxycinnamic acid sorbitol ester: (2R, 3R, 4R, 5S) -2,3,4,5,6-pentahydroxyl (E) -3- (4-hydroxy- 3,5 -dimethoxyphenyl) acrylate
pu? essere sintetizzato in modo analogo al metodo descritto considerando il suo peso molecolare rispettivamente di 166,17 g/mol e 224,21 g/mol. can? be synthesized in a similar way to the described method considering its molecular weight of 166.17 g/mol and 224.21 g/mol respectively.
ESEMPIO 7: Processo secondo la presente invenzione per la preparazione di esteri di acidi benzoici. EXAMPLE 7: Process according to the present invention for the preparation of esters of benzoic acids.
La figura 10 mostra uno schema di formazione dell'estere catalizzato dalla lipasi legato tra acido benzoico e 3 diversi polialcol solidi (eritritolo, xilitolo e sorbitolo): Figure 10 shows a pattern of lipase catalyzed ester formation bonded between benzoic acid and 3 different solid polyalcohols (erythritol, xylitol and sorbitol):
a) estere dell'acido benzoico con eritritolo: (2S, 3R) -2,3,4-triidrossibutil benzoato a) benzoic acid ester with erythritol: (2S, 3R) -2,3,4-trihydroxybutyl benzoate
b) estere dell'acido benzoico con xilitolo: (2S, 3S, 4R) -2,3,4,5-tetraidrossipentil benzoato b) benzoic acid ester with xylitol: (2S, 3S, 4R) -2,3,4,5-tetrahydroxypentyl benzoate
c) estere dell'acido benzoico con sorbitolo: (2R, 3R, 4R, 5S) -2,3,4,5,6-pentaidrossesil benzoato c) benzoic acid ester with sorbitol: (2R, 3R, 4R, 5S) -2,3,4,5,6-pentahydroxyl benzoate
In connessione con i precedenti esempi 1-7, la prova dell'effettiva esterificazione catalizzata dalla lipasi ? stata ottenuta mediante saggi cromatografici (TLC, cromatografia su colonna, HPLC, uHPLC), <1>H- e <13>C-NMR e analisi MS. Le analisi spettroscopiche dimostrano la formazione del legame estereo per le molecole sintetizzate enzimaticamente. Gli esteri hanno mostrato una maggiore affinit? per la fase stazionaria rispetto alle fasi mobili delle cromatografie utilizzate nelle analisi. Questa ? la prova di come la maggiore polarit? degli esteri neoformati abbassi il logP rispetto alle forme acide di partenza, aumentando la solubilit? in acqua dei composti. In connection with the previous examples 1-7, the evidence for effective lipase-catalyzed esterification ? was obtained by chromatographic assays (TLC, column chromatography, HPLC, uHPLC), <1>H- and <13>C-NMR and MS analysis. Spectroscopic analyzes demonstrate ester bond formation for enzymatically synthesized molecules. Esters have shown a greater affinity? for the stationary phase compared to the mobile phases of the chromatographies used in the analyses. This ? the proof of how the greater polarity? of the newly formed esters lower the logP compared to the starting acid forms, increasing the solubility? in compound water.
ESEMPIO 8: Analisi in vitro per testare l'attivit? antimicrobica degli esteri dell'acido sorbico ottenuti mediante il processo della presente invenzione. EXAMPLE 8: In vitro analysis to test the activity antimicrobial of the sorbic acid esters obtained by the process of the present invention.
L'analisi in vitro ? stata eseguita per testare l'attivit? antimicrobica (MIC, Disk Diffusion) di esteri di conservanti alimentari esterificati enzimaticamente con il metodo secondo la presente invenzione. Questi esteri possono essere vantaggiosamente usati per migliorare l'attivit? antimicrobica di conservanti per alimenti e bevande scarsamente solubili in acqua. The in vitro analysis? been performed to test the activity? antimicrobial (MIC, Disk Diffusion) of food preservative esters enzymatically esterified with the method according to the present invention. These esters can be advantageously used to enhance the activity? antimicrobial of poorly water soluble food and beverage preservatives.
Materiali e metodi Materials and methods
? stata utilizzata la tecnica Disk Diffusion (DD), che consente l'identificazione della sensibilit? di diversi microrganismi nei confronti dei composti farmaceutici, ed ? adeguata quando si verifica il meccanismo di resistenza a causa della distruzione dell'agente antimicrobico da parte del microrganismo. La specie batterica era Streptomyces griseus mentre la scelta della specie fungina ? ricaduta su Saccharomyces cerevisiae. Le colture sono state mantenute in laboratorio come slant di agar su un terreno di coltura adatto: cio? GYM (estratto di glucosio-lievito-estratto di malto) per Streptomyces griseus e YMB (brodo di mannitolo di lievito) per il lievito. Per valutare l'attivit? biologica, le colture madri di ciascun microrganismo sono state allestite in piastre di Petri e coltivate fino alla confluenza. ? been used the technique Disk Diffusion (DD), which allows the identification of the sensitivity? of various microorganisms against pharmaceutical compounds, and ? adequate when the resistance mechanism occurs due to the destruction of the antimicrobial agent by the microorganism. The bacterial species was Streptomyces griseus while the choice of the fungal species? fallout on Saccharomyces cerevisiae. The cultures were maintained in the laboratory as agar slants on a suitable culture medium: i.e. GYM (glucose-yeast-malt extract) for Streptomyces griseus and YMB (mannitol yeast broth) for yeast. To evaluate the activity Biologics, mother cultures of each organism were prepared in Petri dishes and grown to confluence.
Quindi, i seguenti composti sono stati testati per la loro attivit? antimicrobica: estere dell'acido sorbico con eritritolo, estere dell'acido sorbico con xilitolo e estere dell'acido sorbico con sorbitolo ottenuti secondo il processo della presente invenzione (vedere Esempio 5). In particolare, in altre piastre di Petri sono stati aggiunti terreno agar appropriato (GYM o YMB) e diverse quantit? dei composti testati. Le concentrazioni finali raggiunte sono riportate nella Tabella 2. So, the following compounds have been tested for their activity? antimicrobial: sorbic acid ester with erythritol, sorbic acid ester with xylitol and sorbic acid ester with sorbitol obtained according to the process of the present invention (see Example 5). In particular, appropriate agar medium (GYM or YMB) and different amounts were added to other Petri dishes. of the tested compounds. The final concentrations achieved are shown in Table 2.
Sono stati utilizzati tre replicati per ciascuna concentrazione. 100 ?l della sospensione contenente 10<6 >unit? formanti colonie (CFU)/mL di cellule microbiche sono stati sparsi su piastre di Petri con appropriato terreno di crescita a base di agar (GYM o YMB). I composti sono stati solubilizzati utilizzando una soluzione di etanolo al 50%. ? stato preparato un controllo negativo aggiungendo quantit? uguali di questa soluzione. La superficie dell'agar ? stata prima inoculata con il microrganismo specifico del test. Quindi, dischi di carta da filtro del diametro di 5 mm sono stati leggermente impregnati utilizzando 10 ?L di soluzione di derivati del farmaco e posti sulla superficie dell'agar. Clotrimazolo [1 mg/mL] e cloramfenicolo [2 mg/mL] sono stati aggiunti ai controlli positivi, mentre i dischi con solvente sono stati realizzati come controlli negativi. Le piastre coltivate sono state mantenute in posizione capovolta durante l'incubazione a 28 ? C per 6 giorni. Le aree in cui il microrganismo di crescita ? stato bloccato dagli agenti antibatterici sono chiamate zone di inibizione. Per determinare l'attivit? antibatterica, i diametri delle zone di inibizione per l'organismo in esame sono stati misurati in millimetri (mm), compreso un diametro del disco di 5 mm, e confrontati con i controlli negativi. Per misurare il diametro della zona di inibizione, il software ImageJ ? stato utilizzato come analizzatore di immagini. Le immagini digitali delle piastre di Petri sono state analizzate dopo la calibrazione del software. La fase di calibrazione correla i pixel di un riferimento nell'immagine con la misura della distanza nel mondo reale (mm). Sono state selezionate zone di inibizione e il diametro della selezione ? stato visualizzato nella finestra "risultati" del software. Three replicates were used for each concentration. 100 ?l of the suspension containing 10<6 >unit? colony forming (CFU)/mL of microbial cells were spread on Petri dishes with appropriate agar-based growth medium (GYM or YMB). The compounds were solubilized using a 50% ethanol solution. ? been prepared a negative control by adding quantity? equal to this solution. The surface of the agar? been first inoculated with the specific test organism. Then, 5 mm diameter filter paper discs were lightly impregnated using 10 µL of drug derivative solution and placed on the agar surface. Clotrimazole [1 mg/mL] and chloramphenicol [2 mg/mL] were added to the positive controls, while solvent discs were made as negative controls. Were the cultured plates held upside down during incubation at 28? C for 6 days. The areas where the microorganism growth ? been blocked by the antibacterial agents are called zones of inhibition. To determine the activity antibacterial, zones of inhibition diameters for the test organism were measured in millimeters (mm), including a disc diameter of 5 mm, and compared to negative controls. To measure the diameter of the zone of inhibition, ImageJ ? been used as an image analyzer. Digital images of Petri dishes were analyzed after software calibration. The calibration step correlates the pixels of a reference in the image with the real-world distance measurement (mm). Have zones of inhibition been selected and the diameter of the selection ? been displayed in the "results" window of the software.
Inoltre, sono state eseguite valutazioni della concentrazione minima inibitoria (MIC). La MIC ? comunemente definita come la concentrazione pi? bassa di composto che inibiva completamente (MIC100) o riduce al 50% (MIC50) la crescita microbica chiaramente visibile dopo l'intero periodo di incubazione, che era di 6 giorni. Questi studi sugli esteri di nuova formazione dell'acido sorbico saranno migliorati con prove di solubilit? in acqua e stabilit? a differenti valori di pH. In addition, minimum inhibitory concentration (MIC) assessments were performed. The MIC? commonly defined as the concentration pi? of compound that completely inhibited (MIC100) or reduced to 50% (MIC50) clearly visible microbial growth after the entire incubation period, which was 6 days. These studies on newly formed sorbic acid esters will be enhanced with solubility tests. in water and stability? at different pH values.
Risultati Results
I risultati ottenuti hanno mostrato aloni di inibizione (per la prova di disk diffusion) maggiori per gli esteri dell'acido sorbico ottenuti secondo il processo della presente invenzione, rispetto agli aloni ottenuti per l'acido sorbico non esterificato. Pertanto, questi risultati mostrano come gli esteri secondo la presente invenzione abbiano una maggiore attivit? antimicrobica rispetto all'ingrediente attivo dell'acido sorbico non esterificato. The results obtained showed higher inhibition zones (for the disk diffusion test) for the sorbic acid esters obtained according to the process of the present invention, with respect to the zones obtained for the non-esterified sorbic acid. Therefore, these results show that the esters according to the present invention have a greater activity? antimicrobial than the active ingredient of non-esterified sorbic acid.
Inoltre, anche le concentrazioni minime inibitorie (MIC) ottenute mostrano che sono necessarie concentrazioni inferiori di esteri dell'acido sorbico secondo la presente invenzione per inibire la crescita del microrganismo rispetto alle concentrazioni richieste dal principio attivo in forma acida. Furthermore, also the minimum inhibitory concentrations (MIC) obtained show that lower concentrations of sorbic acid esters according to the present invention are required to inhibit the growth of the microorganism with respect to the concentrations required by the active ingredient in acid form.
ESEMPIO 9: Analisi in vitro per testare l'attivit? antinfiammatoria degli esteri dell'ibuprofene ottenuti mediante il processo della presente invenzione. EXAMPLE 9: In vitro analysis to test the activity anti-inflammatory properties of the ibuprofen esters obtained by the process of the present invention.
? stata eseguita un'analisi in vitro per testare l'attivit? antinfiammatoria degli esteri dell'ibuprofene esterificati enzimaticamente con il metodo secondo la presente invenzione. ? an in vitro analysis was performed to test the activity? anti-inflammatory properties of the ibuprofen esters enzymatically esterified with the method according to the present invention.
In particolare, sono stati testati i seguenti esteri ottenuti secondo la presente invenzione: In particular, the following esters obtained according to the present invention were tested:
Ibuprofene eritritolo estere Ibuprofen Erythritol Ester
Ibuprofene xilitolo estere Ibuprofen Xylitol Ester
Ibuprofene sorbitolo estere Ibuprofen sorbitol ester
Ibuprofene acido ascorbico estere Ibuprofen ascorbic acid ester
Inoltre, ? stato testato anche ibuprofene glicerolo estere. Moreover, ? Ibuprofen glycerol ester was also tested.
L'attivit? antinfiammatoria dei suddetti composti ? stata testata rispetto ai canonici FANS (ibuprofene). The activity? anti-inflammatory of the aforementioned compounds? been tested against the canonical NSAIDs (ibuprofen).
Materiali e Metodi Materials and methods
La linea cellulare (ATCC? CRL2777?) selezionata ? stata coltivata su piastre da 12 pozzetti. Il giorno successivo le cellule sono state trattate con i FANS, e con concentrazione equimolare degli esteri. TNFalpha, ? stato utilizzato come stimolo dell'infiammazione. L'RNA totale, estratto utilizzando il reagente TRIzol, ? stato retrotrascritto. Il cDNA ? stato il templato per la quantificazione della PCR in tempo reale. La quantit? relativa di ciascun mRNA studiato ? stata normalizzata a GAPDH come gene housekeeping, e i dati sono stati analizzati secondo il metodo 2-??CT. The cell line (ATCC? CRL2777?) selected? was cultured in 12-well plates. The next day the cells were treated with NSAIDs and with an equimolar concentration of the esters. TNFalpha, ? been used as an inflammatory stimulant. Total RNA, extracted using the TRIzol reagent, is been reverse transcribed. The cDNA? was the template for real-time PCR quantification. The quantity? relative of each mRNA studied? was normalized to GAPDH as a housekeeping gene, and data were analyzed according to the 2-??CT method.
Risultati Results
Dati preliminari sulla prova in vitro dei derivati FANS (esteri dell'ibuprofene) sintetizzati con il metodo della presente invenzione dimostrano gli stessi effetti antinfiammatori delle forme acide ma con una migliore solubilit? in acqua. Per gli esteri con maggiore solubilit? l'effetto antinfiammatorio risulta addirittura migliore rispetto ai canonici FANS. Preliminary data on the in vitro test of the NSAID derivatives (ibuprofen esters) synthesized with the method of the present invention demonstrate the same anti-inflammatory effects of the acid forms but with better solubility? in water. For esters with greater solubility? the anti-inflammatory effect is even better than the usual NSAIDs.
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