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    • 专利摘要:
    Compounds for the treatment of diseases caused by the accumulation of oxalate. The present invention relates to the use of salicylic acid derivatives, for the treatment of diseases or pathologies related to the activity of the go and/or prodh2 enzymes, in particular in diseases related to an excess of oxalate, and for the treatment of patients with kidney failure (uremia or hyperazoemia) receiving hemodialysis or peritoneal dialysis, in particular patients treated with ascorbic acid (vitamin c), which is metabolized to oxalate or patients with fibromyalgia and vulvar pain. (Machine-translation by Google Translate, not legally binding)
    公开号:ES2639863A1
    申请号:ES201730326
    申请日:2017-03-10
    公开日:2017-10-30
    发明作者:Mónica DÍAZ GAVILÁN；José Antonio GÓMEZ VIDAL；María Dolores MOYA GARZÓN；Eduardo SALIDO RUIZ；Cristina MARTÍN HIGUERAS；Miguel Xavier FERNANDES
    申请人:Universidad de Granada；Universidad de La Laguna；
    IPC主号:
    专利说明:

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    Salicylic acid is a natural product of plant origin that has multiple known targets not only in plants but also in animals, including humans. Salicylic acid derivatives have been used to treat pain, inflammatory processes and fever. There are also studies that describe the effect
    5 of salicylic acid and its derivatives in the treatment of neurodegenerative diseases, hepatitis C, cancer and dermal disorders, among others [Klessig, DF, Tian, M and Choi, HW (2016). Multiple Targets of Salicylic Acid and Its Derivatives in Plants and Animals. Front Immunol 7: 206].
    10 No references have been found that relate salicylic acid or its derivatives to the ability to reduce oxalate in cells lacking AGT, nor references to the use of such compounds in the treatment of diseases due to the accumulation of oxalate or , in particular, in the treatment of hyperoxaluria.
    15 There are no known references that relate salicylic acid or its derivatives with an inhibitory capacity of GO or PRODH2. 20 BRIEF DESCRIPTION OF THE INVENTION
    The present invention deals with the use of compounds derived from salicylic acid as reducing agents for the excretion of oxalate and / or inhibitors of the activity of GO and PRODH2 enzymes, and therefore of their application for
    25 treatment of diseases taken by the action of GO and / or PRODH2 and / or related to excess oxalate. Among these diseases are, among others, primary hyperoxalurias (PH-1, PH-2 and PH-3), secondary hyperoxaluria or idiopathic renal lithiasis due to calcium oxalate. Additionally, the invention is related to the use of acid derivatives
    30 salicylic for the treatment of patients with renal impairment (uremia or hyperazoemia) receiving hemodialysis or peritoneal dialysis, in particular patients treated with ascorbic acid (vitamin C), which is metabolized to oxalate
    or of patients with fibromyalgia and vulvar pain.
    In another aspect, the invention relates to the use of salicylic acid derivatives; or of
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    image12
    Where: R1 = -H, –CH3
    5 R2 = -H, –CH3 R4 = -H, –NO2, F and R5 = -NO2, -OH, -OCH3, -O-CH2-Ph (4-OCH3), -CH2-O-Ph (3- CF3), -OCH2Ph, -CH2-O-Ph (3,5-F, F), 2-furyl, F, Cl, Br, I.
    10
    More particularly, the salicylic acid derivatives used are selected from the compounds detailed in Table 1:
    Subgr upo Compu thisR 1R2R3R4R5
    TO 74HH2-fury--
    TO 78HH5-formyl-2-furyl--
    TO 76HH3-fury--
    TO 82HH5-hydroxymethyl-2-furyl--
    TO 86HH2-thienyl-
    TO 88HH3-thienyl-
    TO 90HH5-formyl-2-thienyl-
    TO MDM G-919HH5- (piperidinmethyl) -2furyl-
    TO MDM G-927HH5- (3-pyridylmethyl) -2furyl-
    B MDM G-907N H 4H5 - [(4bromophenyl) aminomethyl] -2-furyl-
    B MDM G-911N H 4H5- {4- [4- (5hexinamide) benzoyl] fe nil} aminomethyl-2-furyl-


    B MDM G-915N H 4H5 - [(4nitrophenyl) aminomethyl] 2-furyl-
    B MDM G931PN H 4H5- (benzylaminomethyl) -2furyl-
    B MDM G935PN H 4H5- (propin-1-laminomethyl) -2-furyl-
    C 92HH-Hp- (4methoxyphenylmethox i)
    C 94HH-Ho- [3 (trifluoromethyl) phenyloxymethyl]
    C 96HH-Hp- (benzyloxy)
    C 98HH-Ho- (3,5-Difluorophenyloxim ethyl)
    C MDM G-943HH-Hp- (2-furyl)
    D 73HH2-furyH-
    D 77HH5-formyl-2-furylH-
    D 75HH3-furyH-
    D 79C H 3C H 35-formyl-2-furylH-
    D 80HC H 35-formyl-2-furylH-
    D 81HH5-hydroxymethyl-2-furylH-
    D 83HH5-phenylaminomethyl-2-furylH-
    D 84HH2-furyNo. 2-
    D 85HH2-thienylH-
    D 87HH3-thienylH-
    D 89HH5-formyl-2-thienylH-
    D 302HH5-acetyl-2-thienylH-
    D 306HH5-methyl-2-thienylH-
    D 309HH1-methyl-1H-pyrazol-5-ylH-
    D 310HH4-pyridylH-
    F 91HH-Hp- (4methoxyphenylmethox i)

    F 93HH-Ho- [3 (trifluoromethyl) phenyloxymethyl]
    F 95HH-Hp- (benzyloxy)
    F 97HH-Ho- (3,5-Difluorophenyloxim ethyl)
    F 99HH-Hp-OH
    F 100HH-Hm- (OCH3)
    F 101HH-Hp- (NO2)
    In a preferred embodiment, the salicylic acid derivatives are selected from the group consisting of the compounds of general formula 73, 77, 74 and 78 (table 2).
    Compound Structure CompoundStructure
    73 image13 74 image14
    77 image15 78 image16
    5 Table 2: Preferred use salicylic acid derivatives.
    Pharmaceutical compositions
    In a second aspect, the invention provides pharmaceutical formulations, forms or compositions, hereinafter "compositions of the invention" which comprise as an active ingredient a therapeutically effective amount of at least one salicylic acid derivative. Such formulations may contain any other active ingredient in the treatment of patients with
    15 mentioned diseases or characterized by containing as active ingredient only a derivative of salicylic acid or a combination of derivatives of salicylic acid.


    In different preferred embodiments, the salicylic acid derivative is a compound with general structure I or II, more preferably with general structure A, B, C, D, E or F, even more preferably one of the compounds detailed in Table 1
    5 and even more preferred, one of the compounds detailed in table 2.
    In the sense used in this description, the term "therapeutically effective amount" refers to that amount of a compound that when administered to a mammal, preferably human, is sufficient to produce the treatment of diseases mediated by GO enzyme activity and / or PRODH2, in particular diseases related to excess oxalate such as PH-1, secondary hyperoxaluria, idiopathic renal lithiasis due to calcium oxalate, among others or for the treatment of patients with renal insufficiency (uremia or hyperazoemia) receiving hemodialysis or peritoneal dialysis, in particular patients treated with
    15 ascorbic acid (vitamin C), which is metabolized to oxalate or from patients with fibromyalgia and vulvar pain.
    The amount of a compound that constitutes a therapeutically effective amount will vary, for example, depending on the activity of the specific compound employed; the metabolic stability and duration of action of the compound; the species (preferably human), the clinical form of the human disease, age, body weight, general state of health, sex and diet of the patient; the route of administration, given the possibility of oral or systemic administration; the mode and time of administration; excretion rate, the combination of
    25 drugs; the severity of the particular disorder or pathological condition; and the subject who undergoes therapy, but can be determined by a specialist in the art according to their own knowledge and that description.
    On the other hand, according to the present invention, the "pharmaceutical form" is the
    30 individualized provision to which drugs (active ingredients) and excipients (pharmacologically inactive matter) are adapted to constitute a medicament.
    Thus, said pharmaceutical compositions comprise one or more pharmaceutically acceptable carriers.
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    they have been prepared and / or evaluated biologically are indicated in Table 3. Table 4 also indicates the EC50 found in terms of decreased oxalate production in cultures of mouse hepatocytes Agxt1-KO. 5 Biological evaluation.
    Biological Evaluation Methods
    Development of AGXT and GO enzyme deficient mice: Deficient mice
    10 in AGXT have been previously described. GO-KO mice were obtained according to the procedure described in literature.
    Isolation and culture of hepatocytes: Isolation of hepatocytes from AGT enzyme deficient mice was carried out as described in the literature. A total of 3.0 x 105 cells / well were then cultured in 6-well plates in Williams E medium supplemented with fetal bovine serum (5%), Lglutamine (2 mM), penicillin (100 U / mL), streptomycin (100 µg / mL), insulin (2.2 mUI / mL) and hydrocortisone (0.3 µg / mL). After 5 h the medium was changed to complete Williams E (Biochrom, Cambridge, UK) without serum and the cells were treated with
    20 increasing concentrations of each drug in the presence of 5 mM glycolate. Samples of the culture medium were collected at 24, 48 and 72 h after treatment, for the quantification of oxalate.
    Cell viability and cytotoxicity test: In a 96-well plate,
    25 cultured 1.0 x 104 cells / well. These were treated with the same drug concentrations as in the previous trial. At 24, 48 and 72 h, 20 µL of the Cell Titer 96 Aqueous One Solution reagent (Promega, Madison, Wisconsin) was added and after incubation at 37 ° C for 2 h, absorbance measurements were obtained at 493 nm.
    30 Determination of oxalate: The determination of oxalate excreted in the medium was carried out by testing in the presence of oxalate oxidase using a commercial kit (Trinity Biotech, Co Wicklow, Ireland), following the manufacturer's instructions. GraphPad Prism 5 software was used for graphic representation
    35 of the data as mean ± SD.
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    76 0.89 ± 0.16
    75 1.02 ± 0.3
    77 0.88 ± 0.18
    78 -0.06 ± 0.29a
    80 0.82 ± 0.04
    84 0.86 ± 0.04
    81 0.88 ± 0.01
    82 0.88 ± 0.19
    302 0.89 ± 0.14
    86 0.82 ± 0.01

    85 0.74 ± 0.16
    310 0.88 ± 0.03
    100 0.83 ± 0.03
    99 0.82 ± 0.01
     image22 0.88 ± 0.08
    96 0.8 ± 0.16
    91 0.90 ± 0.16
    97 0.72 ± 0.16
    93 0.62 ± 0.29

    94 0.68 ± 0.21
    Compound EC50 structure (µM) CompoundEC50 structure (µM)
    73 image23 74 image24
    EC50 (24 h) = 9.35 ± 1.34 EC50 (48 h) = 92.19 ± 1.23 EC50 (24 h) = 3.59 ± 1.06 EC50 (48 h) = 7.88 ± 1.04 EC50 (72 h) = 9.2 ± 1.04
    78 image25
    EC50 (24 h) = 3.45 ± 1.17
    EC50 (48 h) = 8.36 ± 1.12
    EC50 (72 h) = 11.19 ± 1.18
    5 Table 4. Representative examples of the compounds for which their found biological activity has been evaluated. Reference compound: CCPST (EC50 (24 h) =
    25.26 µM, EC50 (48 h) = 32.94 µM, EC50 (72 h) = 33.85 µM) 10 Examples of compound synthesis
    General: The reagents were obtained commercially and were used without
    purify. Anhydrous methanol (MeOH) was obtained from commercial sources. He
    Anhydrous dichloromethane (DCM) was obtained by distillation over calcium hydride. Microwave facilitated reactions were performed in a Biotage


    Microwave Initiator with an 8 position arm. NMR spectra were obtained on 300 MHz (Varian INOVA UNITY), 400 MHz (Varian DIRECT DRIVE) or 500 MHz (Varian DIRECT DRIVE) instruments. The chemical shifts (δ) are expressed in ppm and the coupling constants (J) in Hz. 5 In the spectra, the abbreviations correspond to singlet (s), wide singlet (bs), doublet (d), wide doublet (bd ), double doublet (dd), triple triplet (tt), multiplet (m). High resolution mass spectra were recorded on a Waters LCT PremierTM instrument using a flight time analyzer (TOF) with electrospray ionization (ESI) and measured in positive or negative mode. Reactions 10 were monitored by thin layer chromatography (TLC) on aluminum plates (Merica AL Silicagel 60 F254) or by liquid chromatography coupled to a mass spectrometer (LC-MS) on an Agilent 6110 single quadrupole instrument, using a Zorbax Eclipse XDB-C18 4.6 x 150 mm column and electrospray ionization. Purification by flash chromatography was carried out.
    15 out on silicagel (230-400 mesh ASTM). The purity of the final products was checked by HPLC coupled to a diode-array detector (Agilent 1200), using a Zorbax Eclipse XDB-C18 4.6 x 150 mm column. Melting points are not corrected.
    Preparation of salicylic acid derivatives by palladium-catalyzed carbon carbon coupling: a) Compounds 73, 87, 91, 92, 93, 95, 99, 100 and 101: General procedure: A DMF / H2O mixture is prepared in a microwave vial 1/1 in which triphenylphosphine (0.15 equiv), carbonate dissolve
    25 potassium (3.5 equiv) and palladium acetate (0.05 equiv). Next, the corresponding halosalicylate or halosalicylic acid and the corresponding boronic acid or boronate are added sequentially. The mixture is then degassed by bubbling with argon for 15 min and then sealing the vial. The reaction is heated in a microwave instrument to
    30 organic synthesis at 100 ° C for 3 h maintaining stirring during all this time. After this time the reaction is allowed to cool and the filtrate is carried out by washing with methanol. The filtrate is concentrated to dryness using a rotary evaporator and the resulting residue is purified by flash chromatography (elution with mixtures AcOEt: CH3CN: H2O: CH3OH). He
    The product obtained in the chromatographic separation is dissolved / suspended in
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    HRMS (TOF, ES-): Calculated for C11H7O3S (M-H) -: m / z 219.0116. Found 219.0122 (deviation 2.7 ppm).
    P.f. (ºC)  300. 4- [4 ’- (4’ ’- methoxybenzyloxy) phenyl] -2-hydroxybenzoic acid (91): They were used
    5 2-hydroxy-4-iodobenzoic acid (50 mg, 0.189 mmol), 4- (4'methoxybenzyloxy) phenylboronic acid (58.6 mg, 0.227 mmol), PPh3 (7.4 mg, 0.028 mmol), K2CO3 (91.4 mg, 0.662 mmol ), Pd (AcO) 2 (2.12 mg, 0.0095 mmol), DMF: H2O 1: 1 (2 mL). Purification was carried out by flash chromatography (gradient elution using AcOEt: CH3CN: H2O: CH3OH mixture
    10 from 70: 5: 2.5: 2.5 to 60: 10: 10: 10) to obtain compound 91 as a solid. Yield after purification: 17% (11.3 mg). 1H NMR (300 MHz, methanol-d4) δ 7.81 - 7.71 (m, 1H), 7.50 - 7.42 (m, 2H), 7.28 (d, J = 8.5 Hz, 2H), 6.99 - 6.88 (m, 4H), 6.88 - 6.80 (m, 2H), 4.95 (s, 2H,
    15 CH2), 3.70 (s, 3H, CH3). 13C NMR (151 MHz, methanol-d4) δ 131.8, 130.3, 129.4, 117.6, 116.3, 114.9, 114.8, 70.8 (CH2), 55.7 (CH3). HRMS (TOF, ES-): Calculated for C21H17O5 (M-H) -: m / z 349.1076. Found 349.1071 (deviation 1.4 ppm).
    20 P.f. (ºC) = 199.8. 5- [4 '- (4' '- methoxybenzyloxy) phenyl] -2-hydroxybenzoic acid (92): Methyl 5-iodosalicylate (50 mg, 0.180 mmol), 4- (4'methoxybenzyloxy) phenylboronic acid (45 mg , 0.216 mmol), PPh3 (7.1 mg, 0.027 mmol), K2CO3 (87.1 mg, 0.63 mmol), Pd (AcO) 2 (2 mg, 0.009 mmol), DMF: H2O 1: 1 (2
    25 mL) In this case, prior to chromatographic purification, the residue from evaporation of the filtrate was resuspended in methanol. The precipitate was separated from the liquid phase and the latter was discarded. The solid was then purified by flash chromatography (gradient elution with AcOEt: CH3CN: H2O: CH3OH mixtures from 70: 10: 5: 5 until
    30 60: 10: 10: 10). 92 was obtained as a yellowish solid. Yield after purification: 20% (13 mg). 1H NMR (400 MHz, acetone-d6) δ 8.10 (d, J = 2.4 Hz, 1H), 7.80 (dd, J = 8.7,
    2.5 Hz, 1H), 7.57 (d, J = 8.8 Hz, 2H), 7.43 (d, J = 8.6 Hz, 2H), 7.09 (d, J = 8.8 Hz, 2H), 7.04 (d, J = 8.6 Hz , Hz, 1H), 6.96 (d, J = 8.7 Hz, 2H), 5.09 (s, 2H),
    35 3.81 (s, 3H).
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    it was degassed by bubbling with argon for 10 min and the vial was closed. The reaction was programmed in a microwave instrument for organic synthesis at 100 ° C for 3 h. After completion of the reaction, it was filtered by washing with MeOH to remove impurities and the filtrate was concentrated on the rotary evaporator.
    5 The residue was acidified with 10% HCl and purified by flash chromatography (AcOEt / CH3CN / MeOH / H2O 70: 10: 5: 5 mobile phase). Compound 74 was obtained as a brown solid. Yield after purification: 83% (30 mg). 1H NMR (400 MHz, methanol-d4) δ 8.18 (s, 1H), 7.65 (d, J = 7.9 Hz, 1H), 7.48
    10 7.41 (s, 1H), 6.85 (d, J = 8.5 Hz, 1H), 6.55 (d, J = 3.3 Hz, 1H), 6.43 (dd, J = 1.8, 3.4 Hz, 1H). HRMS (TOF, ES-): Calculated for C11H7O4 (M-H) -: m / z 203.0344. Found 203.0350 (deviation 3.0 ppm). c) Compounds 75, 76, 85, 86 and 88:
    15 General procedure: In a sealed tube a solution of potassium carbonate (3 equiv) in water (2 mL / mmol of halosalicylate compound) is prepared to which an equal volume of DMF is added. Next, the compound halosalicylic acid or halosalicylate (1 equiv), boronic acid or boronate (1.2 equiv), triphenylphosphine (0.15 equiv) and palladium acetate (0.05 are added
    20 equiv). The mixture is degassed by bubbling with argon for 10 min and the tube is closed. It is allowed to react in an oil bath at 100 ° C for 24
    h. Once the reaction is over, it is concentrated in the rotary evaporator, resuspended in acetonitrile and filtered. The solid is resuspended in water and acidified with 5% HCl. The solvent is evaporated and the residue obtained is purified by
    25 flash chromatography 4- (3-Furyl) -2-hydroxybenzoic acid (75): 60 mg of 2-hydroxy-4-iodobenzoic acid (0.227 mmol), 52.77 mg of pinacolyl 2-furaboronate (0.272 mmol), 94.12 mg of K2CO3 ( 0.681 mmol), 8.92 mg of PPh3
    (0.034 mmol), 2.47 mg of Pd (OAc) 2 (0.011 mmol), DMF: H2O 1: 1 (2 mL). He
    The reaction crude obtained was purified by flash column chromatography using DCM / MeOH as a mobile phase (gradient 20: 1 → 9: 1) followed by AcOEt / CH3CN / MeOH / H2O (gradient 70: 5: 2.5: 2.5 → 70: 2.5: 1.25: 1.25). Compound 75 was obtained as a brown solid. Yield after purification: 47% (21 mg).
    35 Melting point> 300 ° C


    1H NMR (400 MHz, acetone-d6) δ 8.14 (s, 1H), 7.93 (d, J = 6.8 Hz, 1H), 7.66 (s, 1H), 7.14 (s, 2H), 6.93 (s, 1H) . 13C NMR (101 MHz, acetone-d6) δ 166.92, 162.56, 144.67, 140.88, 139.61, 131.63, 126.02, 116.68, 113.74, 110.38, 108.92. HRMS (TOF, ES-): Calculated for C11H7O4 (M-H) -: m / z 203.0344. Found 203.0347 (1.5 ppm deviation). 5- (3-Furyl) -2-hydroxybenzoic acid (76): 60 mg of methyl 2-hydroxy-5-iodobenzoate (0.216 mmol), 50.25 mg of pinacolyl 3-furaboronate (0.259 mmol), 89.56 mg of K2CO3 were used (0.648 mmol), 8.39 mg of PPh3
    (0.032 mmol), 2.47 mg of Pd (OAc) 2 (0.011 mmol), DMF: H2O 1: 1 (2 mL). The reaction crude obtained was purified by flash column chromatography using DCM / MeOH as a mobile phase (gradient 20: 1 → 9: 1) followed by AcOEt / CH3CN / MeOH / H2O (gradient 70: 5: 2.5: 2.5 → 70: 2.5: 1.25: 1.25). Compound 76 was obtained as a brown solid. Yield after purification: 34% (15 mg). Melting point:> 300 ºC 1H NMR (500 MHz, methanol-d4) δ 8.03 (s, 1H), 7.8 (s, 1H), 7.55 (dd, J = 8.5,
    1.8 Hz, 1H), 7.51 (t, J = 1.7 Hz, 1H), 6.87 (d, J = 8.5 Hz, 1H), 6.73 (d, J = 1.8 Hz, 1H). 13C NMR (126 MHz, methanol-d4) δ 161.8 (C), 144.9 (CH), 144.5 (C), 139.0 (CH), 138.6 (C), 132.4 (CH), 128.7 (CH), 127.3 (C) , 124.4 (C), 118.0 (CH),
    109.5 (CH). HRMS (TOF, ES-): Calculated for C11H7O4 (M-H) -: m / z 203.0344. Found 203.0345 (0.5 ppm deviation). 2-Hydroxy-4- (2-thienyl) benzoic acid (85): 70 mg of 2-hydroxy-4-iodobenzoic acid (0.265 mmol), 40.69 mg of 2-thienylboronic acid were used
    (0.318 mmol), 109.89 mg of K2CO3 (0.795 mmol), 10.49 mg of PPh3 (0.040 mmol), 2.91 mg of Pd (OAc) 2 (0.013 mmol), DMF: H2O 1: 1 (2 mL). Purification by means of flash chromatography was done using DCM / MeOH as mobile phase (gradient elution 20: 1 → 9: 1). Compound 85 was obtained as a yellow solid. Yield after purification: 51% (30 mg). Melting point = 225 ° C
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    Melting point = 222 ºC 1H NMR (400 MHz, acetone-d6) δ 11.04 (s, 1H), 8.15 (d, J = 2.4 Hz, 1H), 7.84 (dd, J = 8.6, 2.3 Hz, 1H), 7.67 - 7.61 (m, 1H), 7.51 (dd, J = 5.0, 2.9 Hz, 1H),
    7.48 - 7.43 (m, 1H), 6.98 (d, J = 8.7 Hz, 1H).
    5 13C NMR (101 MHz, acetone-d6) δ 172.4, 162.0, 141.6, 134.6, 128.3, 128.1, 127.3, 126.6, 120.3, 118.5, 113.1. HRMS (TOF, ES-): Calculated for C11H7O3S (M-H) -: m / z 219.0116. Found 219.0104 (deviation -5.5 ppm).
    d) Methyl 4- (5-Formyl-2-furyl) -2-methoxybenzoate (79).
    10 142.2 mg of K2CO3 (1,029 mmol) in 1 mL of H2O was dissolved in a flask and 0.5 mL of DMF was added. Then 60 mg of 5-bromofuraldehyde (0.343 mmol), 86.31 mg of 3-methoxy-4-methoxycarbonylbenzene boronic acid (0.411 mmol), 13.37 mg of PPh3 (0.051 mmol) were added,
    3.82 mg of Pd (OAc) 2 (0.017 mmol) and 0.5 ml of DMF. The mixture was degassed.
    15 by bubbling with argon for 10 min and reacting for 1 h at 80 ° C. After completion of the reaction, it was concentrated on a rotary evaporator and the reaction crude obtained was purified by flash column chromatography using AcOEt / Hexane as mobile phase (gradient elution 1: 4 → 1: 2). Yield after purification: 57% (51 mg).
    20 Mp: 126 ° C 1 H NMR (400 MHz, CDCl 3) δ 9.69 (s, 1 H), 7.86 (d, J = 8.0 Hz, 1 H), 7.41 (s, 1 H), 7.39 (dd, J = 8.1, 1.5 Hz, 1H), 7.34 (d, J = 3.8 Hz, 1H), 6.94 (d, J = 3.7 Hz, 1H),
    4.00 (s, 3H), 3.91 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 177.53, 166.16, 159.78, 158.01, 152.60, 133.68,
    25 132.55, 123.35, 120.87, 117.24, 109.58, 108.47, 56.45, 52.32. HRMS (TOF, ES +): Calculated for C14H12N2O5Na (M + Na) + :( m / z) 283.0582. Found 283.0591 (deviation 3.2 ppm).
    e) 2-Hydroxy-4- (5-formyl-2-thienyl) benzoic acid (89): In a sealed tube a solution was prepared with 110 mg of K2CO3 (0.795 mmol) in 1 mL of H2O 30 on which They added 0.5 mL of DMF. Then 70 mg of 2-hydroxy-4-iodobenzoic acid (0.265 mmol), 40.62 mg of 5formyl-2-thienylboronic acid (0.318 mmol), 10.49 mg of PPh3 (0.040 mmol), 2.91 mg of Pd (OAc) were added 2 (0.013 mmol) and 0.5 mL of DMF. The mixture was degassed by bubbling with argon for 10 min and the tube was sealed. Be
    35 then allowed to react in a bath at 100 ° C for 24 h. Once finished
    image31
    image32


    The orange product. It was filtered by washing with H2O and the solid obtained was collected. After concentrating on a rotary evaporator, the crude obtained was purified by flash column chromatography using DCM / MeOH 20: 1 → 9: 1 and AcOEt / CH3CN / MeOH / H2O 70: 10: 5: 5 as mobile phase. 80 was obtained as an orange solid.
    5 Yield after purification: 30% (6 mg). 1H NMR (300 MHz, (CD3) 2CO) δ 9.72 (s, 1H), 7.99 (d, J = 8.3 Hz, 1H), 7.67 (s, 1H), 7.65-7.55 (m, 2H), 7.38 (s , 1H), 4.11 (s, 3H). HRMS (TOF, ES-): Calculated for C13H9O5 (M-H) - :( m / z) 245.0450. Found 245.0436 (deviation -5.7 ppm).
    10
    4- (5-hydroxymethyl-2-furyl) -2-hydroxybenzoic acid (81):
    In a round bottom flask, a solution of 4- (5-formyl-2-furyl) -2-hydroxybenzoic acid (77) (33mg, 0.142 mmol) in methanol (2-3 ml) was prepared which was cooled to 0 ° C using a ice bath Subsequently, 15 sodium borohydride (10.8 mg, 0.284 mmol) was added slowly and the reaction was kept under stirring at room temperature until the complete disappearance of the starting product (TLC monitoring) (1 h). The reaction was then acidified to pH 5.0 by adding HCl (5%) and filtering was carried out. The filtrate was concentrated on a rotary evaporator and the residue was purified by flash chromatography.
    20 (elution with AcOEt: CH3CN: H2O: CH3OH gradient gradient from 70: 5: 2.5: 2.5 to 60: 10: 10: 10) to obtain compound 81 as a yellowish solid. Yield after purification: 37.5% (12.5 mg). 1H NMR (400 MHz, methanol-d4) δ 7.86 (d, J = 8.5 Hz, 1H), 7.16-7.09 (m, 2H), 6.76 (d, J = 3.3 Hz, 1H), 6.40 (d, J = 3.3 Hz, 1H), 4.58 (s, CH2, 2H).
    25 HRMS (TOF, ES-) Calculated for C12H9O5: (M-H) -: m / z 233.0450. Found 233.0450 (deviation 0 ppm).
    P.f. (ºC)  300.
    5- (5-Hydroxymethyl-2-furyl) -2-hydroxybenzoic acid (82):
    In a round bottom flask, a solution of 5- (5-formyl-2 acid) was prepared
    30 furyl) -2-hydroxybenzoic acid (78) (40 mg, 0.172 mmol) in methanol (2-3 ml) which was cooled to 0 ° C using an ice bath. Subsequently, sodium borohydride (13.0 mg, 0.344 mmol) was added slowly and the reaction was kept under stirring at room temperature until the complete disappearance of the starting product (TLC monitoring) (3.5 h). The reaction was then acidified to pH 5.0.
    35 by adding HCl (5%) and filtering was carried out. The filtrate is


    Rotavapor concentrated by crude oil was purified by flash chromatography (elution with AcOEt: CH3CN: H2O: CH3OH 60: 10: 10: 10 mixture). Thus 82 (25.6 mg,
    63.6%) as yellowish solid. 1H NMR (400 MHz, methanol-d4) δ 8.32-7.90 (m, 1H), 7.73 (dd, J = 8.7, 2.3 Hz,
    5 1H), 6.92 (d, J = 8.7 Hz, 1H), 6.54 (d, J = 3.3 Hz, 1H), 6.20 (dd, J = 3.3, 0.9 Hz, 1H), 4.10 (s, 2H). 13C NMR (101 MHz, methanol-d4) δ 171.82 (CO), 160.81 (Cq), 152.02 (Cq), 150.83 (Cq), 134.34 (Cq), 130.41 (CH arom), 124.72 (CH arom), 122.70 ( Cq), 117.26 (CH arom), 108.21 (CH arom), 104.37 (CH arom), 26.78 (CH2).
    10 HRMS (TOF, ES-) Calculated for C12H9O5 (M-H) -: 233.0450. Found 233.0442.
    P.f. (ºC):  300.
    4- (5-Phenylaminomethyl-2-furyl) -2-hydroxybenzoic acid (83):
    A solution of 4- (5-formyl-2-furyl) -2-hydroxybenzoic acid (77) (30 mg, 0.129 mmol) in an anhydrous mixture of methanol: dichloromethane 1: 1 (4 mL) was prepared. Activated molecular sieve and aniline (17.7 µL, 0.194 mmol) were then added and the reaction was kept under stirring, protected from light and at room temperature for 1 h. The disappearance at that time of the starting compound was checked
    20 through TLC. The reaction flask was then cooled to 0 ° C for the addition of sodium triacetoxyborohydride (68.3 mg, 0.323 mmol) in a single portion. The reaction was allowed to reach room temperature after which it was kept under stirring for 2 h. The molecular sieve was then removed by filtration and the mixture was acidified to pH 5.0 with HCl (5%). The solvent evaporated
    Then, in rotary evaporator, the crude was purified by flash chromatography (gradient elution with CH2Cl2: CH3OH mixtures from 20: 1 to 6: 1) to obtain 83 as a solid. Yield after purification: 15% (6.1 mg). HRMS (TOF, ES-) Calculated for C18H14NO4 (M-H) -: 308.0923. Found
    30 308.0922.
    P.f. (ºC)  300.
    4- (2-Furyl) -2-hydroxy-5-nitrobenzoic acid (84): 2-hydroxy-4-iodo-5-nitrobenzoic acid (103): 30 mg of 235 hydroxy-4-iodobenzoic acid (0.114) mmol) in 3 mL acetic acid. In cold, it
    image33
    权利要求:
    Claims (1)
    [1]
    image 1
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    公开号 | 公开日
    EP3593803A2|2020-01-15|
    ES2639863B1|2018-09-20|
    EP3593803A4|2020-04-08|
    US20200197418A1|2020-06-25|
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    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    US3558641A|1967-10-06|1971-01-26|Merck & Co Inc|Certain pyridyl salicylic acid derivatives|
    JPH111464A|1997-06-13|1999-01-06|Mitsui Chem Inc|Dicarboxylic acid compounds and production thereof|
    EP1802297B1|2004-10-21|2011-03-30|The Burnham Institute|Compositions and methods for treatment of disease caused by yersinia spp infection|
    US8227500B2|2007-04-11|2012-07-24|Kissei Pharmaceutical Co., Ltd.|5-membered nitrogen containing heterocyclic derivatives and pharmaceutical compositions comprising the same|
    JOP20200115A1|2014-10-10|2017-06-16|Alnylam Pharmaceuticals Inc|Compositions And Methods For Inhibition Of HAO1 ) Gene Expression|
    JP6859323B2|2015-09-02|2021-04-14|サンシャイン・レイク・ファーマ・カンパニー・リミテッドＳｕｎｓｈｉｎｅ Ｌａｋｅ Ｐｈａｒｍａ Ｃｏ．，Ｌｔｄ．|Carboxy-substituted aromatic ring derivatives and their preparation methods and uses|CN109293606A|2018-11-20|2019-02-01|西华大学|The disubstituted furan derivatives of 2,5- and its purposes as SIRT protein inhibitor in medicine preparation|
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