• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
  • 同族专利
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    • 专利摘要:
    Derivatives of lndolin-2-one and its therapeutic use. Derivatives of indolin-2-one of formula (I), where the meaning for r1, r2, r3 and x is the indicated in the description. These compounds are useful as modulators of the enzyme ampk. (Machine-translation by Google Translate, not legally binding)
    公开号:ES2646993A1
    申请号:ES201630826
    申请日:2016-06-17
    公开日:2017-12-18
    发明作者:Ana Castro Morera；Sergio QUESADA SÁNCHEZ；Inés DÍAZ-LAVIADA MARTURET；Nieves RODRÍGUEZ HENCHE；Ágata RAMOS TORRES；Alicia BORT BUENO
    申请人:Consejo Superior de Investigaciones Cientificas CSIC；Universidad de Alcala de Henares UAH；
    IPC主号:
    专利说明:

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    In another embodiment the invention relates to a compound of formula (I) as defined above, where: R1 represents halogen, and preferably where R1 represents F or Cl; R2 represents phenyl optionally substituted by an R4 group, and preferably
    5 where R2 represents Cy1 optionally substituted by a group R5; and Cy1 represents a 5-membered aromatic heterocycle, containing 1 heteroatom selected from O, N and S optionally substituted by a group R5, and preferably where Cy1 is selected from a compound of formula (III), of a compound of formula (IV ) or of a compound of formula (V).
    In another embodiment the invention relates to a compound of formula (I) as defined above, where: X represents halogen, preferably where X represents F or Cl, and more preferably where X represents F;
    R1 represents halogen, and preferably where R1 represents F or Cl; R2 represents phenyl optionally substituted by a group R4, and preferably where R2 represents Cy1 optionally substituted by a group R5; and Cy1 represents a 5-membered aromatic heterocycle, containing 1 heteroatom selected from O, N and S optionally substituted by a group R5, and preferably
    Wherein Cy1 is selected from a compound of formula (III), a compound of formula (IV) or a compound of formula (V).
    In another embodiment the invention relates to a compound of formula (I) as defined above, wherein R5 represents phenyl optionally substituted by a group -NR6R6, -NR6COR6 or -CO2R6.
    In another embodiment the invention relates to a compound of formula (I) as defined above, wherein R5 represents phenyl optionally substituted by a group -CO2R6.
    In another embodiment the invention relates to a compound of formula (I) as defined above, wherein R5 represents phenyl.
    In another embodiment the invention relates to a compound of formula (I) as defined above, wherein:
    image9


    In another embodiment the invention relates to a compound of formula (I) as defined above, where: R1 represents halogen, and preferably where R1 represents F or Cl; R2 represents phenyl optionally substituted by an R4 group, and preferably
    5 where R2 represents Cy1 optionally substituted by a group R5; and R5 represents phenyl optionally substituted by a group -CO2R6, and preferably where R5 represents phenyl.
    In another embodiment the invention relates to a compound of formula (I) as it is
    10 defined above, where: X represents halogen, preferably where X represents F or Cl, and more preferably where X represents F; R1 represents halogen, and preferably where R1 represents F or Cl; R2 represents phenyl optionally substituted by an R4 group, and preferably
    Where R2 represents Cy1 optionally substituted by a group R5; and R5 represents phenyl optionally substituted by a group -CO2R6, and preferably where R5 represents phenyl.
    In another embodiment the invention relates to a compound of formula (I) as defined above, where R 3 represents H.
    In another embodiment the invention relates to a compound of formula (I) as defined above, where: X represents halogen, preferably where X represents F or Cl, and more
    Preferably where X represents F; and R3 represents H.
    In another embodiment the invention relates to a compound of formula (I) as defined above, where: R1 represents halogen, and preferably where R1 represents F or Cl; and R3 represents H.
    In another embodiment the invention relates to a compound of formula (I) as defined above, where: R2 represents phenyl optionally substituted by a group R4, and preferably where R2 represents Cy1 optionally substituted by a group R5; Y
    image10


    R2 represents phenyl optionally substituted by a group R4, and preferably where R2 represents Cy1 optionally substituted by a group R5; R3 represents H; R5 represents phenyl optionally substituted by a group -CO2R6, and preferably
    Where R5 represents phenyl; and Cy1 represents a 5-membered aromatic heterocycle, containing 1 heteroatom selected from O, N and S optionally substituted by a group R5, and preferably where Cy1 is selected from a compound of formula (III), of a compound of formula (IV ) or of a compound of formula (V).
    10
    In another embodiment the invention relates to a compound of formula (I) as defined above, where X represents halogen, preferably where X represents F or Cl, and more
    Preferably where X represents F; R1 represents halogen, and preferably where R1 represents F or Cl; R2 represents phenyl optionally substituted by a group R4, and preferably where R2 represents Cy1 optionally substituted by a group R5; R3 represents H;
    R5 represents phenyl optionally substituted by a group -CO2R6, and preferably where R5 represents phenyl; Cy1 represents a 5-membered aromatic heterocycle, containing 1 heteroatom selected from O, N and S optionally substituted by a group R5, and preferably where Cy1 is selected from a compound of formula (III), of a compound of
    Formula (IV) or a compound of formula (V); R6 represents hydrogen or -CH3.
    In another embodiment the invention relates to a compound of formula (I) as defined above, wherein R 3 represents a group of formula (II).
    In another embodiment the invention relates to a compound of formula (I) as defined above, wherein Cy3 represents phenyl optionally substituted by one or more R7 groups.
    In another embodiment the invention relates to a compound of formula (I) as defined above, where R7 represents -OR6.


    In another embodiment the invention relates to a compound of formula (I) as defined above, wherein: R3 represents a group of formula (III);
    Cy3 represents phenyl optionally substituted by one or more R7 groups; and R7 represents –OR6.
    In another embodiment the invention relates to a compound of formula (I) as defined above, wherein R6 represents hydrogen or -CH3.
    In another embodiment the invention relates to a compound of formula (I) as defined above, selected from:
    Compound StructureName
    2nd image11 3- (pyridin-3-yl-methyl) -2-oxoindole;
    2b image12 3- (pyrrol-2-yl-methyl) -2-oxoindole;
    2 C image13 3- (5-phenylfuran-2-yl-methyl) -2-oxoindole;
    2d image14 5-chloro-3 - [(4-pyrrolidin-1-yl) -benzyl] -2oxoindole;
    2e image15 3- (5-bromofuran-2-yl-methyl) -2-oxoindole;


    2f image16 image17 3 - [(2'-2'-bitiophene) -5-yl-methyl] -2-oxoindole;
    2 g image18 image19 Methyl 3- (5 - ((2-oxoindolin-3-yl) methyl) furan-2yl) benzoate;
    3rd image20 image21 (R, S) -3-Fluoro-3- (pyridin-3-yl-methyl) -2oxoindole;
    3b image22 NHOFNH (R, S) -3-fluoro-3- (pyrrol-2-yl-methyl) -2oxoindole;
    3c image23 image24 (R, S) -3-Fluoro-3- (5-phenylfuran-2-yl-methyl) 2-oxoindole;
    3d ClN H O F N(R, S) -5-Chloro-3-fluro-3 - [(4-pyrrolidin-1-yl) benzyl] -2-oxoindole;
    3e image25 image26 (R, S) -3-Fluoro-3 - [(2, 2'-bitiophene) -5-ylmethyl] -2-oxoindole;
    3f image27 image28 (R, S) -3-Chloro-3- (5-phenylfuran-2-yl-methyl) 2-oxoindole;

    3g image29 (R, S) -3-Chloro-3 - [(2, 2'-bitiophene) -5-ylmethyl] -2-oxoindole;
    3h image30 (R, S) -3- (5 - ((3-fluoro-2-oxoindolin-3yl) methyl) furan-2-yl) methyl benzoate;
    4th image31 (R, S) -1-benzyl-3-fluoro-3- (pyridin-3-ylmethyl) -2-oxoindole;
    4b image32 (R, S) -1-benzyl-3-fluoro-3- (pyrrol-2-ylmethyl) -2-oxoindole;
    4c image33 (R, S) -1-benzyl-3-fluoro-3- (5-phenylfuran-2-methyl) -2-oxoindole;
    4d image34 (R, S) -1-benzyl-5-chloro-3-fluoro-3 - [(4-pyrrolidin-1-yl) -benzyl] -2-oxoindole;
    4e image35 (R, S) -3-Fluoro-1 - ((3-hydroxypyridin-2-yl) methyl) -3- (pyridin-3-yl-methyl) -2-oxoindole;

    4f image36 (R, S) -3-Fluoro-1 - ((3-hydroxypyridin-2-yl) methyl) -3- (pyrrol-2-yl) methyl-2-oxoindole; Y
    4g image37 (R, S) -3 - ((5-phenylfuran-2-yl) methyl-3-fluoro1 - ((3-hydroxypyridin-2-yl) methyl) -2-oxoindole.
    In another embodiment the invention relates to a compound of formula (I) as defined above, selected from: - (R, S) -3-fluoro-3- (pyrrol-2-yl-methyl) -2 -oxoindole (3b);
    5 - (R, S) -1-benzyl-3-fluoro-3- (pyrrole-2-yl-methyl) -2-oxoindole (4b); - (R, S) -5-Chloro-3-fluro-3 - [(4-pyrrolidin-1-yl) -benzyl] -2-oxoindole (3d); and - (R, S) -3-fluoro-3- (5-phenylfuran-2-yl-methyl) -2-oxoindole (3c).
    Another aspect of the invention relates to a pharmaceutical composition comprising a compound of formula (I) as defined above and one
    or more pharmaceutically acceptable excipients thereof.
    Another aspect of the invention relates to the use of a compound of formula (I) as defined above or of a pharmaceutical composition as described.
    15 defined above, for the manufacture of a medicament for the treatment of a disease associated with the modulation of the AMPK enzyme, preferably where the disease is selected from autoimmune, inflammatory, cardiovascular disease, metabolic, neurological syndrome and cancer, more preferably where the disease is selected from type 1 and 2 diabetes, obesity, inflammation,
    20 dyslipidemia, hypertension, hyperglycemia, hypertriglycerimidemia, insulin resistance, epilepsy, stroke, Krabbe / Twitcher diseases, Alzheimer's, parkinson's, huntington and cancer, even more preferably where the disease is cancer; and even more preferably where the disease is prostate cancer, breast cancer, pancreatic cancer, uterine cancer and gliomas.
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    The term "optionally substituted by one or more" means the possibility of a group being substituted by one or more, preferably by 1, 2, 3 or 4 substituents, more preferably by 1, 2 or 3 substituents and even more preferably by 1 or 2 substituents, provided that said group has sufficient available positions
    5 likely to be replaced. If present, said substituents may be the same or different and may be located over any available position.
    The expression "optionally substituted by a group" means the possibility of a group being substituted by 1 substituent located on any position
    10 available.
    When two or more groups with the same numbering appear in a definition of a substituent (for example -NR6R6 and -NR6COR6), this does not mean that they have to be identical. Each of them is independently selected from the list of
    15 possible meanings given for said group, and therefore may be the same or different.
    Throughout the present description, the term "treatment" refers to eliminating, reducing or decreasing the cause or effects of a disease. For the purposes of this
    Invention, treatment includes, but is not limited to, alleviating, reducing or eliminating one or more symptoms of the disease; reduce the degree of disease, stabilize (that is, not worsen) the state of the disease, delay or slow the progression of the disease, relieve or improve the disease status and remit (either total or partial).
    Throughout the description and the claims the word "comprises" and its variants are not intended to exclude other technical characteristics, additives, components or steps.
    The compounds of the invention can be prepared following the following scheme
    one:
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    The compounds of the present invention contain one or more basic nitrogen and could therefore form salts with acids, both organic and inorganic. Examples of such salts include: salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, perchloric acid, sulfuric acid or phosphoric acid; and salts with organic acids, such as methanesulfonic acid, trifluoromethanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, ptoluenesulfonic acid, fumaric acid, oxalic acid, acetic acid, maleic acid, ascorbic acid, citric acid, lactic acid, tartaric acid, malonic acid, acid glycolic, succinic acid and propionic acid, among others. Some compounds of the present
    The invention could contain one or more acidic protons and therefore could also form salts with bases. Examples of such salts include: salts with inorganic cations such as sodium, potassium, calcium, magnesium, lithium, aluminum, zinc, etc .; and salts formed with pharmaceutically acceptable amines such as ammonia, alkylamines, hydroxyalkylamines, lysine, arginine, N-methylglucamine, procaine and the like.
    There is no limitation on the type of salt that can be used, provided that when used for therapeutic purposes they are pharmaceutically acceptable. Pharmaceutically acceptable salts are understood to be those salts that, in medical judgment, are suitable for use in contact with the tissues of human beings or
    20 other mammals without causing undue toxicity, irritation, allergic response or similar. Pharmaceutically acceptable salts are widely known to any person skilled in the art.
    The salts of a compound of formula (I) can be obtained during isolation
    Final and purification of the compounds of the invention can either be prepared by treating a compound of formula (I) with a sufficient amount of the desired acid or base to give the salt in a conventional manner. The salts of the compounds of formula (I) can in turn be transformed into other salts of compounds of formula (I) by ion exchange using a resin of
    30 ion exchange.
    The compounds of formula (I) and their salts may differ in certain physical properties, but are equivalent for the purposes of the invention. All salts of the compounds of formula (I) are included within the scope of the invention.
    35


    The compounds of the present invention can form complexes with solvents in which they are reacted or from which they are precipitated or crystallized. These complexes are known as solvates. As used herein, the term "solvate" refers to a complex of variable stoichiometry formed by a solute (a compound
    5 of formula (I) or a salt thereof) and a solvent. Examples of solvents include pharmaceutically acceptable solvents such as water, ethanol and the like. A complex with water is known as hydrate. Solvates of the compounds of the invention (or their salts), including hydrates, are included within the scope of the invention.
    The compounds of formula (I) can exist in different physical forms, that is to say in amorphous form and crystalline forms. Also, the compounds of the present invention may have the ability to crystallize in more than one way, a characteristic known as polymorphism. The polymorphs can be differentiated by several
    15 physical properties well known to those skilled in the art such as X-ray diffractograms, melting points or solubility. All physical forms of the compounds of formula (I), including all their polymorphic forms ("polymorphs"), are included within the scope of the present invention.
    Some compounds of the present invention could exist in the form of several diastereoisomers and / or several optical isomers. The diastereoisomers can be separated by conventional techniques such as chromatography or fractional crystallization. Optical isomers can be resolved by using conventional optical resolution techniques, to give optically pure isomers. This
    Resolution can be made on synthesis intermediates that are chiral or on the products of formula (I). Optically pure isomers can also be obtained individually using enantiospecific synthesis. The present invention covers both the individual isomers and their mixtures (for example racemic mixtures or mixtures of diastereoisomers), whether obtained by synthesis
    30 like mixing them physically.
    The present invention also relates to a pharmaceutical composition comprising a compound of the invention (or a pharmaceutically acceptable salt or solvate thereof) and one or more pharmaceutically acceptable excipients. The 35 excipients must be "acceptable" in the sense of being compatible with others
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    contain adjuvants such as wetting, suspending, sweetening, flavoring, preservative and pH regulating agents.
    Injectable preparations, according to the present invention, for the
    The parenteral administration comprises sterile solutions, suspensions or emulsions, in an aqueous or non-aqueous solvent such as propylene glycol, polyethylene glycol or vegetable oils. These compositions may also contain adjuvants, such as humectants, emulsifiers, dispersants and preservatives. They could be sterilized by any of the methods known or prepared as
    10 sterile solid compositions that will be dissolved in water or any other sterile injectable medium immediately before use. It is also possible to start from sterile raw materials and keep them in these conditions during the entire manufacturing process.
    For rectal administration, the active ingredient may preferably be formulated as a suppository in an oily base, such as for example vegetable oils or solid semi-synthetic glycerides, or in a hydrophilic base such as polyethylene glycols (macrogol).
    The compounds of the invention can also be formulated for application.
    20 topical for the treatment of pathologies in areas or organs accessible by this route, such as eyes, skin and intestinal tract. Formulations include creams, lotions, gels, powders, solutions and patches in which the compound is dispersed or dissolved in suitable excipients.
    For nasal or inhalation administration, the compound may be formulated as an aerosol from where it is conveniently released with the use of suitable propellants.
    Dosage and dose frequency will vary depending on the nature and
    The severity of the disease to be treated, the age, the general condition and the weight of the patient, as well as the particular compound administered and the route of administration, among other factors. By way of example, an adequate dosage range ranges from about 0.01 mg / kg to about 100 mg / kg per day, which can be administered as a single dose or in several doses.
    35
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    FIG 5a and FIG 5b. Variation of cell viability of HepG2 human hepatocarcinoma cells at different concentrations of the compounds and incubation times indicated. HepG2 cells were incubated with the different compounds
    5 at the doses and times indicated after which cell viability was determined by MTT. The results are referred to that of the cells treated with vehicle, taken as 100% viability and are means ± D.E. of three experiments performed in duplicate.
    10 FIG 6a and FIG 6b. Phosphorylation levels of AMPK enThr172 (p-AMPK), total AMPK, phosphorylation of ACC in Ser79 (p-ACC) and total ACC after treatment with the compounds under study for 1 h at 25 µM in human Hepatocarcinoma HepG2 cells.
    15 FIG. 6c and FIG 6d. Phosphorylation levels of AMPK enThr172 (p-AMPK), total AMPK, phosphorylation of ACC in Ser79 (p-ACC) and total ACC after treatment with the compounds under study for 1 h at 25 µM in human Hepatocarcinoma HepG2 cells followed of 1mM of AICAR during the last 30 minutes.
    20 FIG 7a and FIG 7b. AMPK phosphorylation levels in HT172 (p-AMPK), total AMPK, ACC phosphorylation in Ser79 (p-ACC) and total ACC after treatment with the compounds under study for 1 h at 25 µM, followed by 5 µM dorsomorphine in human cells of Hepatocarcinoma HepG2. 25 EXAMPLES Example 1 General method of synthesis of the compounds of general formula (3) and
    (4)
    The compounds 3a-h and 4a-g were synthesized according to the synthetic route that is collected in the following reaction scheme:
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    265 ° C. 1 H-NMR (300 MHz, CDCl 3) δ (ppm): 7.70-7.62 (m, 2H), 7.56-7.47 (m, 1H), 7.48-7.42 (m, 1H) , 7.39 (dd, J = 3.8, 1.1 Hz, 1H), 7.37-7.17 (m, 2H), 7.15-6.97 (m, 2H), 6.87 (d , J = 7.8 Hz, 1H). HPLC: tR = 5.59 (98%). MS (ES, positive mode) m / z 310.2 [M-H] +.
    (E, Z) -3- (5-bromofuran-2-yl-methylidene) -2-oxoindole (1f) Following the experimental procedure described for this type of compound, at a solution of 1 g (7.52 mmol) of 2-Oxoindole is added 1.31 g of 5-bromo-2furaldehyde (7.52 mmol), resulting in the reaction 1.45 g (67%) of a yellow solid.
    P. f. 230 ° C. 1H-NMR (300 MHz, CDCl3) δ (ppm): 8.36 (d, J = 7.9 Hz, 1H, H-Ar), 7.68 (s, 1H, NH), 7.36-7 , 18 (m, 2H, H-Ar), 7.11 (td, J = 7.7, 1.2 Hz, 1H, H-Ar), 6.93-6.79 (m, 2H, H- Ar), 6.57 (d, J = 3.5 Hz, 1H, CH). HPLC: t R = 4.70 (95%). MS (ES, positive mode) m / z 292.2 [M-2H] +. General procedure for the synthesis of 3- (arylmethyl) -2-oxoindoles (2a-f)
    To a solution of the corresponding 5-amino-3-phenyl-1H-pyrazole (1 eq.) In methanol (10 mg / mL) is added NaBH4 (5 eq.) For 30 min. After the addition, the mixture is stirred at room temperature overnight. Once the reaction is over, a volume of water approximately equal to half of the crude is added and the mixture is extracted three times with an equal volume of ethyl acetate. The organic phases are combined, dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure. The residue is purified by column chromatography on silica gel using as eluent a mixture of hexane: ethyl acetate (2: 1).
    3- (pyridin-3-yl-methyl) -2-oxoindole (2a)
    Following the general procedure of synthesis of 3- (arylmethyl) -2-oxoindoles, start from 3- (pyridin-3-yl-methylene) -2-oxo-indole (250 mg, 1.12 mmol) and NaBH4 (212 mg, 5.56 mmol), obtaining 80 mg (31%) of a pale yellow solid. P.f. 115-117 oC (bibl. 139-142 oC). 1 H NMR (300 MHz, CDCl 3) δ (ppm): 10.32 (s, 1 H, NH), 8.34 (d, J = 3.2 Hz, 1 H, H-Ar), 8.28 (s, 1H, H-Ar), 7.50 (d, J = 7.9 Hz, 1H, H-Ar), 7.21 (dd, J = 7.8, 4.7 Hz, 1H, H-Ar) , 7.11 (t, J = 7.6 Hz, 1H, H-Ar), 7.04 (d, J = 7.4 Hz, 1H, H-Ar), 6.89 (t, J = 7 , 4 Hz, 1H, H-Ar), 6.71 (d, J = 7.5 Hz, 1H, H-Ar), 3.86 (t, J = 6.1 Hz, 1H, H3), 3 , 32 - 3.24 (m, 1H, CH2), 3.07 (dd, J = 13.9, 6.7 Hz, 1H, CH2). HPLC: t R = 3.76 (98%). MS (ES, positive mode) m / z 225.3 [M + H] +.
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    General procedure for the synthesis of 3- (arylmethyl) -3-chloro-2-oxoindoles (3 fg)
    To a solution of 3- (arylmethyl) -2-oxoindole (1 eq.) In dichloromethane (10 mL) is added
    5 triethylamine (0.6 eq.). The mixture is cooled to 0 ° C and Nchlorosuccinimide (1.2 eq.) Dissolved in dichloromethane (5 mL) is added slowly. The resulting mixture is stirred for 1 h at room temperature. After completion of the reaction, the solvent is removed under reduced pressure and the residue is purified by column chromatography on silica gel hexane: ethyl acetate (3: 1).
    10 (R, S) -3-Chloro-3- (5-phenylfuran-2-yl-methyl) -2-oxoindole (3f) Following the general synthesis procedure for 3- (arylmethyl) -3-chloro-2oxoindoles and starting from 60 mg (0.21 mmol) of (R, S) -3- (5-phenylfuran-2-yl-methyl) -2oxoindole, 33.7 mg of N-chlorosuccinimide (0.25 mmol) and 18 μL (0.13 mmol) of
    15 triethylamine gives 50 mg of a pale brown solid. P. f. 139-141 ° C. 1H-NMR (300 MHz, CDCl3) δ (ppm): 8.98 (s, 1H, NH), 7.26 (m, 8H, H-Ar), 6.74 (d, J = 7.8 Hz , 1H, H-Ar), 6.28 (t, J = 3.3 Hz, 1H, H-Ar), 5.99 (d, J = 3.3 Hz, 1H, H-Ar), 3, 76-3.39 (m, 2H, CH2). HPLC: t R = 5.26 (98%). MS (ES, positive mode) m / z 324.2 [M-H] +.
    20 (R, S) -3-chloro-3 - [(2, 2'-bitiophene) -5-yl-methyl] -2-oxoindole (3g) Following the general procedure for the synthesis of 3- (arylmethyl) - 3-Chloro-2-oxoindoles, starting from 30 mg (0.10 mmol) of (R, S) -3 - [(2'-2'-bitiophene) -5-yl-methyl] -2-oxoindole, of 15.44 mg (0.12 mmol) of N-chlorosuccinimide and 9 µL (0.62 mmol) of triethylamine to obtain 16 mg (48%) of a brown oil. 1 H-NMR (300 MHz, CDCl 3) δ (ppm):
    25 8.18 (s, 1H, NH), 7.36 (d, J = 7.5 Hz, 1H, H-Ar), 7.26 (s, 1H, H-Ar), 7.18-7 , 06 (m, 2H, H-Ar), 6.99-6.89 (m, 2H, H-Ar), 6.87-6.78 (m, 2H, H-Ar), 6.58 ( d, J = 3.7 Hz, 1H, H-Ar), 4.12 (d, J = 7.1 Hz, 1H, CH2), 3.72 (d, 1H, CH2). HPLC: t R = 5.32 (98%). MS (ES, positive mode) m / z 346.2 [M-H] +.
    30 General procedure for synthesis of N-substituted derivatives of 3- (arylmethyl) -3fluoro-2-oxoindoles (4a-g) To a solution of the corresponding 3- (arylmethyl) -3-fluoro-2-oxoindole (1 eq) in Anhydrous DMF (12 mL / g) is added NaH (1.1 eq. When the brominated derivative is benzyl bromide and 2.1 eq. When it is 2-bromomethyl-3-hydroxypyridine hydrochloride). After 10
    35 min. at room temperature, the corresponding brominated derivative (1 eq) is added and
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    权利要求:
    Claims (7)
    [1]
    image 1
    image2
    image3

    [21]
    21. The compound according to claim 1, selected from:
    Compound StructureName
    2nd image4 3- (pyridin-3-yl-methyl) -2-oxoindole;
    2b image5 3- (pyrrol-2-yl-methyl) -2-oxoindole;
    2 C image6 3- (5-phenylfuran-2-yl-methyl) -2-oxoindole;
    2d image7 5-chloro-3 - [(4-pyrrolidin-1-yl) -benzyl] -2oxoindole;
    2e image8 3- (5-bromofuran-2-yl-methyl) -2-oxoindole;
    2f image9 3 - [(2'-2'-bitiophene) -5-yl-methyl] -2-oxoindole;
    2 g image10 Methyl 3- (5 - ((2-oxoindolin-3-yl) methyl) furan-2yl) benzoate;
    3rd image11 (R, S) -3-Fluoro-3- (pyridin-3-yl-methyl) -2oxoindole;
    44

    3b image12 NHOFNH (R, S) -3-fluoro-3- (pyrrol-2-yl-methyl) -2oxoindole;
    3c image13 image14 (R, S) -3-Fluoro-3- (5-phenylfuran-2-yl-methyl) 2-oxoindole;
    3d ClN H O F N(R, S) -5-Chloro-3-fluro-3 - [(4-pyrrolidin-1-yl) benzyl] -2-oxoindole;
    3e image15 image16 (R, S) -3-Fluoro-3 - [(2, 2'-bitiophene) -5-ylmethyl] -2-oxoindole;
    3f image17 image18 (R, S) -3-Chloro-3- (5-phenylfuran-2-yl-methyl) 2-oxoindole;
    3g image19 image20 (R, S) -3-Chloro-3 - [(2, 2'-bitiophene) -5-ylmethyl] -2-oxoindole;
    3h image21 image22 (R, S) -3- (5 - ((3-fluoro-2-oxoindolin-3yl) methyl) furan-2-yl) methyl benzoate;
    4th image23 image24 (R, S) -1-benzyl-3-fluoro-3- (pyridin-3-ylmethyl) -2-oxoindole;
    Four. Five

    4b image25 (R, S) -1-benzyl-3-fluoro-3- (pyrrol-2-ylmethyl) -2-oxoindole;
    4c image26 (R, S) -1-benzyl-3-fluoro-3- (5-phenylfuran-2-methyl) -2-oxoindole;
    4d image27 (R, S) -1-benzyl-5-chloro-3-fluoro-3 - [(4-pyrrolidin-1-yl) -benzyl] -2-oxoindole;
    4e image28 (R, S) -3-Fluoro-1 - ((3-hydroxypyridin-2-yl) methyl) -3- (pyridin-3-yl-methyl) -2-oxoindole;
    4f image29 (R, S) -3-Fluoro-1 - ((3-hydroxypyridin-2-yl) methyl) -3- (pyrrol-2-yl) methyl-2-oxoindole; Y
    4g image30 (R, S) -3 - ((5-phenylfuran-2-yl) methyl-3-fluoro1 - ((3-hydroxypyridin-2-yl) methyl) -2-oxoindole.
    [22]
    22. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 21 and one or more pharmaceutically acceptable excipients thereof.
    46

    [23]
    23. Use of a compound of formula (I) according to any one of claims 1 to 21 or of a pharmaceutical composition according to claim 22, for the manufacture of a medicament for the treatment of a disease associated with
    5 AMPK enzyme modulation.
    [24]
    24. The use according to claim 23, wherein the disease is selected from autoimmune, inflammatory, cardiovascular, metabolic, neurological syndrome and cancer.
    10
    [25]
    25. The use according to any of claims 23 or 24, wherein the disease is selected from type 1 and 2 diabetes, obesity, inflammation, dyslipidemia, hypertension, hyperglycemia, hypertriglycerimidemia, insulin resistance, epilepsy, stroke, Krabbe diseases / Twitcher, Alzheimer, Parkinson,
    15 huntington and cancer.
    [26]
    26. The use according to any of claims 23 to 25, wherein the disease is cancer.
    The use according to claim 26, wherein the cancer is selected from prostate cancer, breast cancer, pancreatic cancer, uterine cancer and gliomas.
    47
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    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    WO2011069298A1|2009-12-11|2011-06-16|F. Hoffmann-La Roche Ag|Novel cyclopropane indolinone derivatives|
    WO2015091937A1|2013-12-19|2015-06-25|Sanofi|Oxindole derivatives, preparation thereof and therapeutic use in the treatment of ampk-related diseases|
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