[go: up one dir, main page]

WO2016037298A1 - Procédé de synthèse énantiosélective d'acide 2(s)-amino-6-boronohexanoïque (abh) et purification - Google Patents

Procédé de synthèse énantiosélective d'acide 2(s)-amino-6-boronohexanoïque (abh) et purification Download PDF

Info

Publication number
WO2016037298A1
WO2016037298A1 PCT/CL2015/050035 CL2015050035W WO2016037298A1 WO 2016037298 A1 WO2016037298 A1 WO 2016037298A1 CL 2015050035 W CL2015050035 W CL 2015050035W WO 2016037298 A1 WO2016037298 A1 WO 2016037298A1
Authority
WO
WIPO (PCT)
Prior art keywords
bpb
abh
dichloromethane
acid
resulting
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/CL2015/050035
Other languages
English (en)
Spanish (es)
Inventor
Marcelo Daniel PREITE
Juan Manuel MANRIQUEZ MUJICA
Jordan Mauricio CORREA VARGAS
Rodrigo Manuel ITURRIAGA AGUERA
Paola Cecilia CASANELLO TOLEDO
Bernardo Javier KRAUSE LEYTON
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Pontificia Universidad Catolica de Chile
Original Assignee
Pontificia Universidad Catolica de Chile
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Pontificia Universidad Catolica de Chile filed Critical Pontificia Universidad Catolica de Chile
Publication of WO2016037298A1 publication Critical patent/WO2016037298A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
    • C07F5/02—Boron compounds

Definitions

  • the present invention relates to a process for enantioselective synthesis and purification of 2 (S) -Amino-6- Boronohexanoic acid (ABH), and the preparation of the corresponding synthetic intermediates en route to them.
  • L-arginine is catabolized in two different ways: the arginases catalyze their hydrolysis to L-ornithine and urea, in what would be the first step of ureogenesis, and NO synthases (NOS) catalyze oxidation to L-citrulline, and NO, in the biosynthesis of NO (Guoyao Wu and Sidney M. Morris, Jr., "Arginine metabolism: nitric oxide and beyond", B ⁇ ochem. J. 336, (1998) 1-17).
  • NOS NO synthases
  • ABS 2 (S) -Amino-6-Boronohexanoic acid
  • ABH 2 (S) -Amino-6-Boronohexanoic acid
  • ABH comes from analyzing the X-ray structure of the ternary arginase-ornithine-borate complex, in which it was shown that the borate anion Tetracoordinated perfectly mimics the tetrahedral transition state or states in the catalytic reaction (Zoltan F. Kanyo, Laura R. Scolnick, David E. Ash, David W. Christianson, Nature 383, (1996) 554-557).
  • ABH comes from conceptually replacing the guanidino group of the arginine side chain with a boronate.
  • ABH is a borate analogue, or isostero, of arginine, and the first synthetic arginase inhibitor. It is proposed that ABH's high affinity for arginase is a consequence of its structural similarity with that of the proposed transition state for arginine hydrolysis (Ricky Baggio, Daniel Elbaum, Zoltan F. Kanyo, Patrick J. Carroll, R. Christopher Cavalli , David, E. Ash, David W. Christianson, "Inhibition of Mn2 + 2-Arginase by Borate Leads to the Design of a Transition State Analogue Inhibitor, 2 (S) -Amino- 6-boronohexanoic Acid", J. Am. Chem.
  • the first ABH synthesis was also carried out, which was made from the tert-butyl ester of the protected N-BOC glutaric acid, which was reduced in its side chain to the corresponding primary alcohol, which was subjected to oxidation of Swern to give the aldehyde, which in turn was methylated by means of a Wittig reaction.
  • the present invention proposes an alternative preparation method to those known, and has the following advantages over previously used methods:
  • Gly-Ni-BPB complex as a chiral auxiliary, which undergoes deprotonation with strong base (NaOH) thereof at room temperature, and an alkylation of the resulting anion with 4-bromobut-l-eno, to obtain ABH, or 5- bromopent-l-eno, to obtain the ABH homolog, 4-bromobut-l -ino, and to give an unsaturated derivative of ABH, those that gave rise to mixtures of the corresponding alkylated diastereomeric Ni complexes, which were purified by careful ion exchange chromatography, thus separating the major diastereomers, which were used to give the optically pure amino acids corr sponges This preparation involves making difficult separations and purifications, which complicate the preparation of substantial quantities of the final products.
  • the present invention does not require the conversion of the brominated derivative of catecolborane into one of pinacolborane (which allows the introduction of the side chain), which shortens the sequence of obtaining this sensitive precursor of the molecule, and which requires manipulation in an inert atmosphere. Instead, a method for the effective separation of the catechol in the final phase of purification, alternative to that described above, is described.
  • the obtaining of Gly-Ni BPB complex is also indicated in detail, which requires care in the choice of reagents and reaction conditions, details not available in the previous literature.
  • the method of the present invention part of commercial L-proline, which is subjected to N-benzylation by treatment with benzyl chloride in isopropanol in the presence of base at 50 ° C to, after neutralizing, produce (S) -iV -Benzylproline (BP) raw, mixed with KC1.
  • the base tripotassium phosphate
  • the base is also added in portions. After a while a rather abundant and notorious precipitate begins to appear. The suspension is a brown color, and it is left stirring until the complete disappearance of the amine (which is the limiting reagent) verified by analytical TLC chromatography.
  • the treatment with saturated solution of ammonium chloride removes excess acid chloride that may be present, and the base BPB is extracted with dichloromethane, to give a reddish brown oil, which is purified by recrystallization of the corresponding hydrochloride, by direct treatment with HC1, and adding acetone to the aqueous phase so that the brown-yellowish salt precipitates.
  • the BPB-Ni-Gly complex is prepared from base BPB, instead of hydrochloride, by heating with an excess of hydrated nickel nitrate and glycine, in a suspension in a C1-C3 alcohol, for example, methanol at Reflux. Once the set is heated, a strong base, such as KOH or another similar one, is added to then reflux for at least 6-7 hours, after which a TLC chromatographic analysis shows the disappearance of the BPB, and then proceed to neutralize and extract, obtaining the complex of Ni, solid red vermilion, which is purified by chromatography column preparation
  • the side chain preparation required for the enantioselective alkylation reaction is performed for the lower 3-carbon alkyl chain, and can also be performed for alkyl chains of up to 6 carbon atoms, as reported by Zixia Feng * and Mark Hellberg, "Synthesis of novel prostaglandins containing a boronate in the a chain", Tetrahedron Letters 41, (2000) 5813-5816
  • the Ni complex was added, in anhydrous THF solution, on the brominated side chain and in the presence of potassium t-butoxide, used as a base, previously cooled to -50 ° C, and kept the whole under nitrogen, with vigorous stirring. , and maintaining the low temperature throughout the process. Once the addition is complete, it is stirred cold, and the whole is allowed to reach room temperature, under a nitrogen atmosphere. The resulting vermilion red complex is extracted and neutralized in aqueous medium. During this procedure, a part of the side chain catechol is lost. The crude complex thus obtained is treated with excess HC1 1.5N in a C1-C5 alcohol, for example, methanol, at reflux.
  • a C1-C5 alcohol for example, methanol
  • the reaction mixture consists of inorganic salts, the desired ABH, BPB and catechol, which is difficult to treat and separate.
  • the crude product solution is concentrated in a rotary evaporator, whereby the BPB precipitates, as hydrochloride, and this is removed by filtration. This is subsequently extracted with dichloromethane to remove the BPB and catechol that may be present.
  • ammonia is added, and it is extracted again with dichloromethane, in order to extract remains that could remain of BPB, as a base and catechol.
  • the ammonia phase containing ABH, Ni salts and NH 4 C1 is concentrated on a rotary evaporator, and chromatographed on Dowex 50w x8 ion exchange resin (acid form), first with deionized water, and then with 2N ammonia.
  • the ABH-containing fractions (such as their ammonium salt) are combined, and evaporated on a rotary evaporator, to obtain a white solid (48% from the BPB-Ni-Gly complex).
  • Figure 1 shows the arginase activity of synthetic ABH versus commercial standards of ABH, and BEC.
  • the present invention proposes a method of preparation that is an alternative to known preparations, and that part of L- ⁇ ; proline commercial, proceeding to its N-benzylation by treatment with benzyl chloride in isopropanol in the presence of base at 50 ° C, and subsequent neutralization, which produced solid BP precipitated together with KC1.
  • the extractive treatment of this solid with dichloromethane allowed to easily separate soluble BP, from insoluble KC1, with very good yield (90% dry BP).
  • the resulting BP should be meticulously dried by treatment in a high vacuum desiccator over phosphorus pentoxide, for 2-3 days, or alternatively, in a vacuum oven at about 40-50 ° C for several hours.
  • the resulting very dry BP was suspended in dry dichloromethane, the suspension was cooled to 0 ° C, and thionyl chloride was added dropwise, and then gently heating, to about 30 ° C, to get all the solid to dissolve.
  • the resulting yellow solution was allowed to stir several hours (or even overnight), under a stream of dry nitrogen, in order to remove most of the HC1 produced during the reaction.
  • the acid chloride solution was heated to about 30 ° C, and the o-aminobenzophenone (which is the limiting reagent in this reaction) was added carefully in a stream of nitrogen and in portions in a defect of 2 -3% with respect to BP, and with continuous magnetic stirring, to favor its dissolution.
  • the base tripotassium phosphate
  • the base can be added in 3-4 portions. It was observed that after a while it began to appear quite abundant precipitate. It is important to take care of having a vigorous magnetic stir at all times. This suspension is gradually taking a brown color, and left stirring for at least 12 to 15 hours, or until the analysis Chromatographic showed the disappearance of the limiting amine.
  • the treatment with saturated ammonium chloride solution removed the excess acid chloride present, and the base BPB, such as a reddish brown oil, was extracted with dichloromethane, which was purified by recrystallization of the corresponding hydrochloride, by treatment with HC1, and acetone, which easily precipitates salt, brown-yellowish.
  • the BPB'HCl showed by NMR analysis that it actually consists of a mixture of the two possible protonated, diastereoisomeric forms in proline N.
  • BPB-Ni-Gly complex it was more convenient to use BPB base, instead of the hydrochloride, which was heated together with excess hydrated nickel nitrate (1.8 equivalents) and excess glycine (5 equivalents), in a suspension in methanol at reflux. Once the set was hot, KOH was added (7 equivalent) in small portions, and waiting for the previous portion to react before proceeding to add a new portion. Once the addition was complete, it was left at least 6-7 hours under reflux, neutralized and extracted, and the Ni complex was obtained as a vermilion red solid, which was purified by preparative column chromatography (90%).
  • the Ni complex was added, in anhydrous THF solution, on the brominated side chain (in excess of 44% over the complex) and potassium t-butoxide used as a base (slightly more than 300% excess) previously cooled at -50 ° C, and kept the assembly under nitrogen, with vigorous agitation, and at that temperature during the entire addition process, using syringes, needles and cannulas, as appropriate.
  • the complex must be added slowly (drip), in order to allow the whole to cool. Once the addition is complete, it is left for 15 minutes while stirring in the cold, and the whole is allowed to slowly reach room temperature, for several hours, and always under a nitrogen atmosphere.
  • the resulting vermilion red complex is extracted and neutralized in aqueous medium.
  • the crude anterior complex is treated with e: 1.5N HC1 stop in methanol at reflux for 7 hours, after which analytical chromatography demonstrated the absence of the Ni complex.
  • the reaction mixture consists in this point of inorganic salts, the desired ABH, BPB and catechol, which is difficult to treat and separate Unless the following steps are followed carefully.
  • the crude product solution was concentrated on a rotary evaporator to the minimum possible volume, whereby almost all of the BPB precipitates, as hydrochloride, which is removed by filtration. This was extracted with dichloromethane, to remove almost all of the BPB and, above all, from the catechol that might be present, and which complicates the further purification of the final product.
  • Ammonia was added to the aqueous phase, and it was extracted again with dichloromethane, in order to extract remains of BPB, as a base, and catechol, which could remain.
  • the ammonia phase containing the ABH, Ni salts, and NH 4 C1
  • the ABH-containing fractions (as ammonium salt) are combined, and evaporated on a rotary evaporator, for a white solid (48% from the BPB-Ni-Gly complex).
  • arginase activity was analyzed as a function of urea generated in total protein extracts obtained from human placentas.
  • protein extraction from homogenized placenta was performed using Hepes-Tris lysis buffer (10 mM Hepes, buffered to pH 6.95 with Tris) in the presence of protease inhibitors.
  • From 100 g of total protein arginase activity was tested by adjusting the total volume to 90 ⁇ with lysis buffer and incubating at 55 ° C for 10 minutes in the presence of 5 mM MnCl 2 , in order to induce the activation of the enzyme arginase, in a total volume of 95 ⁇ .
  • Enzymatic activity was stopped by the addition of 400 ⁇ of acid mixture H 2 SO 4 / H 3 PO 4 / H 2 O at 1/3/7 ratio and the urea produced was incubated by incubating the resulting solution at 95 ° C for 45 minutes in the presence of 25 ⁇ of 9% ⁇ -isonitrosopropyrophenone in ethanol.
  • Urea quantification was performed by spectrophotometry by measuring the absorbance at 540 nm and integrating the results into a standard urea curve of 100 to 1000 ⁇ .
  • Arginase activity was defined as the concentration of urea generated by protein mass in 1 hour (nmol of urea ⁇ Tg of protein -1 ⁇ hour -1 ) and the results were expressed as arginase activity relative to the control condition (ie in the absence of arginase inhibitors).
  • Figure 1 shows the arginase activity under control conditions (0), in the presence of ABH synthesized by the proposed methodology (1 - 500 ⁇ ), and against commercial inhibitors ABH and BEC (bars yellow). Both commercial and synthesized compounds reduce urea production by approximately 50% compared to the control. Additionally, the synthesized ABH shows an inhibition of arginase activity as a function of concentration, reaching comparable levels of inhibition to those observed by commercial variants at similar concentrations.
  • the benzyl chloride is loaded into the addition funnel (48 ml, 52.8 g, 0.417 mol), which was dripped at the rate of 1 drop every 5 seconds (giving an addition time of about 3 hours) Stirring is maintained for at least an additional 6 hours, always at the same temperature.
  • the appearance of a copious white precipitate (of KC1) is observed, which gives the mixture a creamy appearance, and that care must be taken to stir vigorously at all times.
  • the resulting suspension is neutralized to pH 5-6 (measured by pH paper), by the addition of strong acid, such as concentrated HC1 (about 55 ml), and filtered through a funnel with a medium-sized filter frit.
  • strong acid such as concentrated HC1 (about 55 ml)
  • CHC1 3 50 ml
  • the resulting suspension was filtered again by the same frit. This procedure was repeated several times, and the resulting combined chlorinated filtrates were evaporated in vacuo, to thereby give crude BP (69.5 g, 0.339 mol, 90% yield), which was dried under high vacuum in the presence of phosphorus pentoxide, and was used in the next stage without further purification.
  • the flask is loaded with previously dried BP (4.71 g, 23 millimoles), which is suspended in dichloromethane (100 ml).
  • the resulting whitish-milky suspension is stirred magnetically in an ice-water bath, and thionyl chloride (1.65 ml) is added dropwise by syringe, and carefully (HC1 gas can be produced, and some internal pressure, especially if no precautions were taken when drying the starting material).
  • the suspension acquires a yellowish-greenish tint at that point when thionyl chloride is added, and its transformation must be gradually observed in a true transparent, although yellowish solution. If the presence of abundant solid in suspension is observed, it is a clear sign that an additional amount of thionyl chloride is required (a sign that the acid was not very dry), which should be estimated in each case, and proceed in such a way that the excess is the minimum indispensable. It is convenient to leave this solution stirring a few hours, or even until the next day, to allow the expulsion of excess HC1, and renew the nitrogen atmosphere.
  • the resulting solution which may be somewhat colored, was gently heated to about 40 ° C, 2-aminobenzophenone (4,074 g, 20.7 mmol) was added, in portions, and then tripotassium phosphate (12.18 g, 57.4 millimoles), always with vigorous agitation. Soon there is an appearance of abundant precipitate, and it is important to keep the heating to prevent it from becoming very thick, and prevent magnetic stirring. The suspension gradually takes a brown color.
  • Heating and stirring is maintained for at least 12-15 hours, until the next day, and the disappearance of the entire starting amine is verified by chromatographic analysis (for example, TLC using an eluent of ethyl acetate-hexane 1: 1, will show BPB with an Rf close to 0.7, while BP gives an Rf close to 0.0).
  • chromatographic analysis for example, TLC using an eluent of ethyl acetate-hexane 1: 1, will show BPB with an Rf close to 0.7, while BP gives an Rf close to 0.0).
  • BPB «HC1 (4.25 g, 10.1 mmol) was dissolved in water (20 ml) containing a heavy and carefully measured amount of KOH (567 mg, 10.1 mmol). The mixture is allowed to stir, and extracted with CH 2 C1 2 (x 5 ml). The combined organic phases are dried over Na 2 S0 4 , filtered, and evaporated, to give BPB base (3.88 g, 100%), as a dark reddish brown oil.
  • the suspension is heated to about 40-50 ° C, to improve the solubility of the components.
  • the mixture acquires a dark greenish color, and it heat to reflux.
  • the KOH is weighed separately (15.31 g, or 272, 12 millimoles, that is 7 times in excess), and it is incorporated in small portions of the solid into the hot reaction mixture. It is advisable to wait between two successive additions, so that no large amount of precipitate appears, which prevents proper agitation. As the base is added, it is observed that the original greenish brown color of the BPB changes to a blood red color, and some greenish precipitate appears (probably basic Ni salts). As the reaction progresses, the precipitate disappears, but in the beginning it can be a problem.
  • the product is sensitive to air, and quickly darkens due to exposure to air and / or moisture. A small portion was taken, which was dissolved in deuterochloroform, and a characterization was achieved by means of nuclear magnetic resonance.
  • the resulting crude product a very thick and viscous liquid of dark color, solidifies upon cooling, and is purified according to the aforementioned for the lower 3-carbon homolog by vacuum distillation in a short-pass system (Zixia Feng * and Mark Hellberg, "Synthesis of novel prostaglandins containing a boronate in the a chain", Tetrahedron Letters 41, (2000) 5813-5816), for which the system was first connected at high vacuum (of the order of 1 ⁇ ), with the system still cold, and the temperature of the heating bath was raised, thus allowing the elimination of volatile waste first.
  • the desired product was distilled at about 80 ° C, under these conditions. Extreme caution is crucial during distillation, since the distillate solidifies when distilling, and the system can become clogged.
  • the desired product (38 g, 69% yield) was obtained as a white crystalline solid, which was kept in an inert atmosphere at all times, in a dry box under nitrogen.
  • the BPB-Ni-Gly red complex (6.10 g, 12.25 millimoles) was weighed in a second 2-ml 250-ml balloon, and this solid, dissolved in anhydrous tetrahydrofuran, was transferred (using a total of about 180 my, in several portions), with the help of a cannula, under nitrogen at all times, and very slowly, taking care that the reaction mixture is kept cold at all times. The reaction mixture, under these conditions is dark green. Once the entire complex is added, the reaction mixture is allowed to stir at -50 ° C for 15 minutes. The cold bath is removed, and the system is allowed to slowly take room temperature, until the next day, always under a nitrogen atmosphere.
  • the resulting blood red solution is neutralized with acetic acid (8 ml) and water (200 ml). It is extracted with dichloromethane (50 ml x4), and the combined organic extracts are dried with anhydrous sodium sulfate, filtered, and evaporated in vacuo, to give the crude, red alkylated complex (10.8 g), which It is used in the next step without purification.
  • the aqueous phase was diluted with water (50 ml), concentrated ammonia (about 30 ML, up to pH 9, by indicator paper) was added, and extracted again with dichloromethane (50 ml x2), which extracts base BPB, and catechol remains still present.
  • the aqueous ammonia phase is evaporated in vacuo, on a rotary evaporator, to dryness, to give crude ABH (a greenish solid), such as ammonium salt, together with a large amount of ammonium chloride, and the presence of nickel salts.
  • a chromatographic column is assembled with Dowex 50w x8 exchange resin (25 mm diameter glass column, with about 20 cm resin height), acidic form (the column is treated with 1.5 N HC1, then washed with deionized water to neutral pH, and observe the absence of chlorides in eluate, when treated with 1% silver nitrate solution in ethanol), the crude of the last preparation is sown, and it is eluted first with distilled water until observing that the eluate it is free of chlorides (test with 1% silver nitrate in ethanol), and once that is achieved, ABH is eluted with 2N aqueous ammonia.
  • ABH ninhydrin
  • TLC acetic acid-butanol 1-4 v / v, Rf ⁇ 0.10

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un procédé de synthèse énantiosélective et de purification de l'acide 2(S)-amino-6-boronohexanoïque (ABH) et la préparation des intermédiaires de synthèse correspondants. Le procédé comprend la préparation d'ABH à partir de BPB-Ni-Gly, lequel est traité avec une base forte dans un solvant adéquat, puis mis à réagir avec du 2-(4-bromo-alkyle inférieur)benzo[d] [1,3,2]dioxaborol, l'alkyle inférieur étant un alkyle ayant de 1 à 6 atomes de carbone, de préférence due 2-(4-bromo-butil)benzo[d][1,3,2]dioxaborol, sous agitation, en atmosphère d'azote et avec un bain cryogénique à basse température (à -50°C), puis laissé se réchauffer jusqu'à température ambiante par retrait du bain cryogénique, avant d'être soumis à une neutralisation en milieu aqueux avec un acide organique faible, et à une extraction au dichlorométhane, l'extrait organique résultant étant séché, puis filtré et évaporé sous vide. Le complexe alkylé résultant est dissous dans un alcool C1-C5, avec ajout d'un acide chlorhydrique, et mis à reflux sous atmosphère d'azote, puis refroidi à température ambiante, et concentré pour obtenir la précipitation de (S)-2-[N-(N'-benzylprolyle) amino]benzophénone (BPB), en tant que sel de chlorhydrate, lequel est filtré et soumis à une extraction au dichlorométhane, et après dissolution dans de l'eau, la phase aqueuse du filtrat est traitée à l'ammoniaque concentrée jusqu'à atteindre un pH 9, et soumise à une nouvelle extraction au dichlorométhane, et la phase aqueuse ammoniacale est évaporée sous vide jusqu'à séchage, pour ainsi obtenir un ABH brut, comme le sel d'ammonium, qui est ensuite purifié par chromatographie d'échange d'ions. L'invention concerne également un procédé de préparation du complexe Gly-Ni-BPB, 2-(4-bromobutyl)benzo[d][1,3,2]dioxaborol, utilisé comme agent alkylant sous forme de chaîne latérale comprenant du bore, et de (S)-N-benzylproline (BP).
PCT/CL2015/050035 2014-09-11 2015-08-20 Procédé de synthèse énantiosélective d'acide 2(s)-amino-6-boronohexanoïque (abh) et purification Ceased WO2016037298A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CL2403-2014 2014-09-11
CL2014002403A CL2014002403A1 (es) 2014-09-11 2014-09-11 Metodo para la preparacion enantioselectiva y purificacion del acido 2(s)-amino-6-boronohexanoico (abh) a partir de la disolucion de bpb-ni-gly en tetrahidrofurano, neutralizacion y posterior extraccion con diclorometano, disolucion en un alcohol c1-c5, enfriamiento para lograr la precipitacion de bpb, obtencion de abh y su posterior purificacion.

Publications (1)

Publication Number Publication Date
WO2016037298A1 true WO2016037298A1 (fr) 2016-03-17

Family

ID=53404015

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CL2015/050035 Ceased WO2016037298A1 (fr) 2014-09-11 2015-08-20 Procédé de synthèse énantiosélective d'acide 2(s)-amino-6-boronohexanoïque (abh) et purification

Country Status (2)

Country Link
CL (1) CL2014002403A1 (fr)
WO (1) WO2016037298A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12054500B2 (en) 2018-03-05 2024-08-06 Arcus Biosciences, Inc. Arginase inhibitors
US12226425B2 (en) 2018-11-16 2025-02-18 Arcus Biosciences, Inc. Inhibitors of ARG1 and/or ARG2

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6387890B1 (en) * 1997-10-10 2002-05-14 Trustees Of The University Of Pennsylvania Compositions and methods for inhibiting arginase activity

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6387890B1 (en) * 1997-10-10 2002-05-14 Trustees Of The University Of Pennsylvania Compositions and methods for inhibiting arginase activity

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
COLLET S. ET AL.: "Synthesis and evaluation of w-borono-a-amino acids as active-site probes of arginase and nitric oxide synthases.", JOURNAL OF THE CHEMICAL SOCIETY, PERKIN TRANSACTIONS, vol. 1, 2000, pages 177 - 182, XP008162032, DOI: doi:10.1039/a908140b *
VADON-LEGOFF, S. ET AL.: "Improved and High Yield Synthesis of the Potent Arginase Inhibitor: 2(S)-Amino-6-boronohexanoic Acid.", ORGANIC PROCESS RESEARCH & DEVELOPMENT, vol. 9, no. 5, 2005, pages 677 - 679 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12054500B2 (en) 2018-03-05 2024-08-06 Arcus Biosciences, Inc. Arginase inhibitors
US12226425B2 (en) 2018-11-16 2025-02-18 Arcus Biosciences, Inc. Inhibitors of ARG1 and/or ARG2

Also Published As

Publication number Publication date
CL2014002403A1 (es) 2015-01-09

Similar Documents

Publication Publication Date Title
Song et al. A single fluorescent chemosensor for multiple target ions: recognition of Zn2+ in 100% aqueous solution and F− in organic solvent
JPWO2012111818A1 (ja) 蛍光プローブ
Zhang et al. A low dose, highly selective and sensitive colorimetric and fluorescent probe for biothiols and its application in bioimaging
An et al. Fluorescence sensor for sequential detection of zinc and phosphate ions
Zhao et al. A new selective chemosensor based on phenanthro [9, 10-d] imidazole-coumarin with sequential “on-off-on” fluorescence response to Fe3+ and phosphate anions and its application in live cell
EP3096143B1 (fr) Agent de détection d'ions de fer (ii) et procédé de détection l'utilisant
CN105712964B (zh) 一种基于香豆酰肼的硫醇荧光探针的制备方法及应用
JP5688826B2 (ja) カルパイン活性検出蛍光プローブ
CN102993047A (zh) 快速高选择性硫化氢比色探针
CN108276990A (zh) 一种区分GSH、Cys、NAC荧光探针及其制备方法和应用
Biancalana et al. Ruthenium Arene Complexes with α‐Aminoacidato Ligands: New Insights into Transfer Hydrogenation Reactions and Cytotoxic Behaviour
WO2016037298A1 (fr) Procédé de synthèse énantiosélective d'acide 2(s)-amino-6-boronohexanoïque (abh) et purification
ES2298395T3 (es) Indicadores de la actividad enzimatica.
ES2715309T3 (es) Complejos metálicos dinucleares injertados, y su uso como sensores de micropartículas celulares
Wan et al. A new xanthene-based fluorescent probe with a red light emission for selectively detecting glutathione and imaging in living cells
CN102268249A (zh) 一种可用肉眼检测汞离子的荧光探针及其制备方法和应用
CN106929006A (zh) 一种以萘酰亚胺为母核的识别半胱氨酸和同型半胱氨酸荧光探针及其制备与应用
Sinha et al. Hydrazine responsive molecular material: optical signaling and mushroom cell staining
Zhang et al. Water-soluble BODIPY derivative as a highly selective “Turn-On” fluorescent probe for hydrogen sulfide in living cells
Mahapatra et al. Hg2+-selective “turn-on” fluorescent chemodosimeter derived from glycine and living cell imaging
WO2007149105A2 (fr) Capteurs à base de fluorescéine destinés au pistage d'oxyde nitrique dans des cellules vivantes
CN110467582B (zh) 一种用于铜离子检测的点亮型近红外荧光探针及制备方法
CN110437283B (zh) 一种钾离子荧光探针及其制备方法和应用
EP1923397B1 (fr) Acides aminés et peptides fluorés
ES2297373T3 (es) Sustratos enzimaticos, medios de cultivo que los contienen, utilizacion para detectar una actividad aminopeptidasa y/o diferenciar bacterias gram negativas.

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 15839511

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 15839511

Country of ref document: EP

Kind code of ref document: A1