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WO2008007979A1 - Dérivés de l'acide benzoïque ayant des propriétés immunomodulatrices et anticancéreuses - Google Patents

Dérivés de l'acide benzoïque ayant des propriétés immunomodulatrices et anticancéreuses Download PDF

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Publication number
WO2008007979A1
WO2008007979A1 PCT/NZ2007/000178 NZ2007000178W WO2008007979A1 WO 2008007979 A1 WO2008007979 A1 WO 2008007979A1 NZ 2007000178 W NZ2007000178 W NZ 2007000178W WO 2008007979 A1 WO2008007979 A1 WO 2008007979A1
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Prior art keywords
dioxo
piperidinyl
amino
carbonyl
acid
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PCT/NZ2007/000178
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English (en)
Inventor
Brian Desmond Palmer
Lai-Ming Ching
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Auckland Uniservices Limited
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Publication of WO2008007979A1 publication Critical patent/WO2008007979A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
    • C07D211/86—Oxygen atoms
    • C07D211/88—Oxygen atoms attached in positions 2 and 6, e.g. glutarimide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention is concerned with certain benzoic acid derivatives and their use in the treatment of neoplastic disorders.
  • the present invention is concerned with carboxybenzoyl glutamic acid analogues and their uses.
  • CGI iV-(o-carboxybenzoyl)glutamic acid imide
  • compositions that are stable at a broad range of pHs would be significantly advantageous as they could potentially be administered orally without loss of activity.
  • compounds with increased metabolic stability would also be highly desirable, as this would provide longer exposure to the active agent following administration.
  • the object of the present invention is to ameliorate one or more disadvantages of current immunomodulatory and cancer therapies or to provide a useful alternative.
  • R 5 can be selected from -COOH, -COR 11 , -CONR 12 Ri 3 , -CONR 14 R 15 NR 16 R 17
  • CONR 18 R 19 OR 2O5 CONR 21 R 22 SO 2 R 23 , N- N 5 COOR 24 , R 1 to R 4 and R 6 to R 24 can be independently selected from hydrogen, halogen, amino, nitro, cyano, alkyl thioether, alkyl sulfone, alkyl sulfoxide, substituted alkyl, substituted cycloalkyl, hydroxy, alkyl ether, carboxylic acid and acid derivatives such as amide and ester, aryl thioether, aryl sulfone, aryl sulfoxide, aryl ether, NR 25 R 26, aromatic and . heteroaromatic ring,
  • R 25 and R 26 can be independently selected from hydrogen, substituted alkyl and substituted cycloalkyl, substituted aryl and substituted heteroaryl, R 1 and R 2 , or R 2 and R 3 , or R 3 and R 4 can be fused to generate an additional ring system(s), which may be heterocyclic or carbocyclic (saturated or unsaturated), in the glutarimide ring B two substituents (the same or different) can be attached to a single ring carbon atom, wherein, when R 12 R 13 , Ri 6 R 17 and R 25 R 26 are alkyl they may be joined together to form a ring system which may additionally contain one or more heteroatoms selected from oxygen, sulphur, nitrogen or selenium and wherein one or more carbonyl groups in the formula may be replaced by thiocarbonyl.
  • R 1 and R 2 , or R 2 and R 3 , or R 3 and R 4 can be fused to generate an additional ring system(s), which may be heterocyclic or carb
  • Preferred compounds can be either racemic or comprise a single enantiomer or diastereomer (where this is possible).
  • the preferred compounds of the present invention can be selected from: 2- ⁇ [(2,6-Dioxo-3-piperidinyl)amino]carbonyl ⁇ -3,4,5,6-tetrafluorobenzoic acid, 2-Amino-6- ⁇ [(2,6-dioxo-3-piperidinyl)amino]carbonyl ⁇ benzoic acid, 3-Ammo-2- ⁇ [(2,6-dioxo-3-piperidinyl)amino]carbonyl ⁇ benzoic acid, ⁇ - ⁇ -(Dimethylam ⁇ ethyy- ⁇ -Cl ⁇ -dioxo-S-piperidiny ⁇ -S ⁇ jS ⁇ -tetrafluoro-N 1 - methylphthalamide, iV 1 -(2,6-Dioxo-3-pi ⁇ eridinyl)-N 2 -(2-hydroxyethyl)-N 2 -niethylphthalamide, N-(2,6-Dioxo
  • a method of modulating the immune system comprising administering to a subject a compound according to the first aspect or a composition according to the second aspect.
  • a method of inhibiting angiogenesis comprising administering to a subject requiring such treatment a compound according to the first aspect or a composition according to the second aspect.
  • a method of treating a neoplastic disorder comprising administering to a subject requiring such treatment a compound according to the first aspect or a composition according to the second aspect.
  • the neoplastic disorder is of haematopoietic origin na d most preferably it is multiple myeloma.
  • the neoplsatic disorder may also be a tumour, for example a vascularised tumour and the like.
  • a sixth aspect there is provided a method of inhibiting cytokine production by contacting a cell capable of producing one or more cytokines with a compound according to the first aspect or a composition according to the second aspect.
  • FIG. 1 Inhibition by FCGI of TNF production induced with lipopolysaccharide - (LPS) or DMXAA in mice
  • Figure 5 Inhibition of IL-6 production by human multiple myeloma cells by CGI, FCGI and compound 19a
  • the present invention is based in part on studies which demonstrate the ability of the compound 2- ⁇ [(2,6-Dioxo-3-piperidinyl)amino]carbonyl ⁇ benzoic acid (1), also referred to as CGI, to modulate cytokines and inhibit cancer growth.
  • the present invention concerns analogues of CGI, which are useful in cancer therapy and as immunomodulators.
  • the compounds of the present invention have a general formula as follows:
  • R 5 can be selected from -COOH, -COR 11 , -CONR 12 Ri 3 , -CONR 14 R 15 NRi 6 R 17 ,
  • CONRi 8 R 19 OR 20 , CONR 2 iR 2 2SO 2 R 2 3 , N N , COOR 24 , R 1 to R 4 and R 6 to R 24 can be independently selected from hydrogen, halogen, amino, nitro, cyano, alkyl thioether, alkyl sulfone, alkyl sulfoxide, substituted alkyl, substituted cycloalkyl, hydroxy, alkyl ether, carboxylic acid and acid derivatives such as amide and ester, aryl thioether, aryl sulfone, aryl sulfoxide, aryl ether, NR 25 R 265 aromatic and heteroaromatic ring.
  • R 25 and R 26 can be independently selected from hydrogen, substituted alkyl and substituted cycloalkyl, substituted aryl and substituted heteroaryl. Furthermore two substituents R 1 and R 2 , or R 2 and R 3 , or R 3 and R 4 can be fused to generate an additional ring system(s), which may be heterocyclic or carbocyclic (saturated or unsaturated). When R 12 R 13 , Ri 6 Ri 7 and R 25 R 26 are alkyl they may be joined together to form a ring system which may additionally contain one or more heteroatoms such as oxygen, sulphur, nitrogen or selenium.
  • the glutarimide ring B two substituents (the same or different) can be attached to a single ring carbon atom.
  • Preferred compounds can be either racemic or comprise a single enantiomer or diastereomer (where this is possible).
  • One or more carbonyl groups in the formula may be replaced by thiocarbonyl.
  • the activities and/or physical properties as a drug of the analogues of the present invention can be significantly improved over the native CGI compound by the incorporation of appropriate substitutions around the benzene ring and/or the glutarimide ring.
  • addition of one or more halogen atoms, preferably fluorine to the benzene ring has dramatically improved the potency of CGI.
  • the tetrafiuoro-substituted derivative (2) is especially active. Incorporation of amino functionality to the benzene ring is also beneficial. In particular, compounds such as (3) and (4) show improved activity.
  • the carboxylic acid group in (1) may be replaced by other functionality generally known in the field of medicinal chemistry as "acid isosteres", such as acyl sulfonamide, tetrazolyl, sulfonyltriazolyl, and the like.
  • prodrugs of the acid group such as ester derivatives may be prepared to modulate physical properties.
  • Examples of preferred compounds of the present invention include but are not limited to:
  • the present invention employs well recognized and accepted cell culture systems to demonstrate the cytokine modulatory activities of the CGI analogues.
  • the relevant methodology is also described in US patent application 11/454,420, which is incorporated in its entirety herein by reference.
  • the compounds and compositions of the present invention are suitable for treatment of neoplastic disorders as well as modulating cytokine production and the immune system.
  • the term "neoplastic disorder” is intended to encompass any benign or malignant condition or tumour, including vascularised solid tumours.
  • vascularised solid tumour is used to describe any solid tumour, whether benign or malignant, which relies on ample blood supply for its establishment and growth.
  • the tissue or organ location, or tissue origin, of such tumours is not material to the compositions and methods of the present invention as long as there is reliance by the tumour on its blood supply.
  • the compositions and methods of the present invention may be used to treat colon cancers, breast cancers, liver cancers, lung cancers, brain tumours, ovarian tumours, prostate cancers, testicular cancers, uterine tumours and the like.
  • neoplastic disorder is also intended to encompass benign or malignant conditions of haematopoietic origin, such as different haematopoietic malignancies.
  • the compounds of the present invention may be used for the treatment of multiple myeloma, a variety of leukaemias and similar malignancies.
  • the compounds of the present invention may be formulated into pharmaceutical preparations by any number of processes well known in the art and may include injectable, topical, oral, slow release and other suitable dosage forms and preparations.
  • Routes of administration include, but are not limited to, intravenous (iv), intraperitoneal, subcutaneous, intracranial, intradermal, intramuscular, intraocular, intrathecal, intracerebral, intranasal, transmucosal, or by infusion orally, rectally, via iv drip, patch and implant. Intravenous routes are particularly preferred.
  • compositions suitable for injectable use include sterile aqueous solutions (where water soluble) and sterile powders for the extemporaneous preparation of sterile injectable solutions.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol and liquid polyethylene glycol, and the like), suitable mixtures thereof and vegetable oils.
  • the prevention of the action of micro-organisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thirnerosal and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.
  • Sterile injectable solutions are prepared by incorporating the composition in accordance with the invention in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by, for example, filter sterilization or sterilization by other appropriate means.
  • Dispersions are also contemplated and these may be prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above.
  • a preferred method of preparation includes a vacuum drying and freeze-drying technique that yields a powder of the active ingredient together with any additional desired ingredient from a previously sterile-filtered solution.
  • composition in accordance with the invention may be orally administered, for example, with an inert diluent or with an assimilable edible carrier, or it may be enclosed in hard or soft shell gelatin capsule, or it may be compressed into tablets.
  • the composition may be incorporated with excipients and used in the form of an ingestible tablet, a buccal tablet, a troche, a dragee, a capsule, an elixir, a suspension, a syrup, a wafer and the like.
  • Such preparations should contain at least 0.01 % by weight, more preferably 0.1% by weight, even more preferably 1% by weight of a composition in accordance with the invention.
  • compositions or preparations according to the present invention are prepared so that an oral dosage unit form contains between about 0.1 ng and 2000 mg of the composition in accordance with the present invention.
  • the ingestible tablet, buccal tablet, troche, dragee, capsule, elixir, suspension, syrup, wafer or the like may also contain the components as listed hereafter: a binder, for example, gum, acacia, corn starch or gelatin; an excipient, for example, dicalcium phosphate; a disintegrating agent, for example, corn starch, potato starch, alginic acid and the like; a lubricant, for example, magnesium stearate; and a sweetening agent, for example, sucrose, lactose or saccharin and a flavouring agent such as peppermint, oil of wintergreen, or cherry flavouring.
  • a binder for example, gum, acacia, corn starch or gelatin
  • an excipient for example, dicalcium phosphate
  • a disintegrating agent for example, corn starch, potato starch, alginic acid and the like
  • a lubricant for example, magnesium stearate
  • the dosage unit form When the dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier. Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit. For instance, a tablet, a pill, or a capsule may be coated with shellac, sugar or both.
  • a syrup or elixir may contain, in addition to the composition in accordance with the invention, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavouring such as cherry or orange flavour. Any material used in preparing any dosage unit form should be pharmaceutically pure and substantially non-toxic in the amounts employed.
  • the composition in accordance with the present invention may be incorporated into a sustained-release preparation or formulation.
  • the present invention also extends to forms suitable for topical application such as creams, lotions and gels.
  • the formulation may further comprise one or more excipients suitable for nasal or pulmonary delivery.
  • the excipients may be sugars, for example, lactose, mannitol, xylitol, trehalose, dextrose or other pharmaceutically acceptable sugars.
  • Further excipients may include one or more surfactants, preferably a surfactant which is solid at ambient temperatures, for example, 25 0 C.
  • a carboxylic acid, for example, oleic acid may be employed.
  • Alternative surfactants include lecithin and sorbitan esters.
  • Desiccant excipients may be employed.
  • Delay release excipients may also be used to provide for release of the composition over - H - a longer period of time in vivo.
  • An excipient of low water solubility may be used, for example, a pharmaceutically acceptable polymer such as a cellulose derivative, polyvinyl pyrollidone or a sugar derivative.
  • pH stabilisers antioxidants and flavouring agents. These may be chosen, if necessary, from standard pharmaceutical anti-oxidants, for example, alpha-tocopherol or ascorbyl palmitate, or pH modifiers, for example, citric acid or tris buffer or physiologically acceptable sodium salts, to enable the long tenn stability of the composition to be improved over a composition without these excipients.
  • a dosage form in accordance with the present invention may incorporate an external excipient for improved flow characteristics of the dry powder composition.
  • suitable external excipients include lactose, mannitol, trehalose or other sugars or mixtures thereof.
  • compositions of the present invention may also include an antimicrobial preservative which can be selected from the group consisting of benzalkonium chloride, methylparaben, sodium benzoate, benzoic acid, phenyl ethyl alcohol, mixtures thereof, and the like.
  • an antimicrobial preservative which can be selected from the group consisting of benzalkonium chloride, methylparaben, sodium benzoate, benzoic acid, phenyl ethyl alcohol, mixtures thereof, and the like.
  • the surfactant is selected from the group consisting of: polysorbate 80 NF, polyoxyethylene 20 sorbitan monolaurate, polyoxyethylene 4 sorbitan monolaurate, polyoxyethylene 20 sorbitan monopalmitate, polyoxyethylene 20 sorbitan monostearate, polyoxyethylene 4 sorbitan monostearate, polyoxyethylene 20 sorbitan tristearate, polyoxyethylene 5 sorbitan monooleate, polyoxyethylene 20 sorbitan trioleate, polyoxyethylene 20 sorbitan monoisostearate, sorbitan monooleate, sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate, sorbitan trilaurate, sorbitan trioleate, sorbitan tristearate, mixtures thereof, and the like.
  • the tonicity agent is selected from the group consisting of: dextrose, lactose, sodium chloride, mixtures thereof, and the like.
  • the suspending agent is selected from the group consisting of: microcrystalline cellulose, carboxymethylcellulose sodium NF, polyacrylic acid, magnesium aluminum silicate, xanthan gum, mixtures thereof, and the like.
  • Pharmaceutically acceptable carriers and/or diluents include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, use thereof in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions.
  • Dosage unit form refers to physically discrete units suited as unitary dosages for the mammalian subjects to be treated; each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
  • the specification for the novel dosage unit forms of the invention are dictated by and directly dependent on (a) the unique characteristics of the active material and the particular therapeutic effect to be achieved and (b) the limitations inherent in the art of compounding.
  • Phenyl 2,6-dioxo-3-piperidinylcarbamate (15) N,N-Dimethylaminopyridine (100 mg 5 0.89 mmol), followed by 1,1'- carbonyldiimidazole (5.78 g, 0.036 mol) were added to a suspension of N- carbobenzyloxyglutamine (14) (5.00 g, 0.018 mol) in dry p-dioxane (100 ml) and the mixture was stirred at room temperature for 10 min, then refluxed under nitrogen for 17 h. The solvent was removed in vacuo and the residue was partitioned between ethyl acetate and water.
  • Triethylamine (0.65 mi, 4.54 mmol) was added to a suspension of 16 (0.37 g, 2.27 mmol) in dry tetrahydrofuran (40 ml) and the mixture was stirred at room temperature for 10 min.
  • Tetrafluorophthalic anhydride (17) (0.50 g, 2.27 mmol) was added and stirring was continued at room temperature for 48 h.
  • the reaction mixture was partitioned between ethyl acetate and water and the aqueous portion was acidified with 2N HCl and extracted with ethyl acetate (5 times). The combined extracts were worked up to give an oil which was dried well in vacuo and then triturated with diethyl ether until crystallization began.
  • JV-(2,6-Dioxo-3-piperidinyl)-2-(l-pyrroIidinylcarbonyI)benzainide (21) Pivaloyl chloride (0.62 ml, 5.01 mmol) was added dropwise at 5 0 C to a solution of (20) (1.0Og, 4.56 mmol) and triethylamine (0.70 ml, 5.02 mmol) in dichloromethane (20 ml) and the solution was stirred at this temperature for 1 h. Triethylamine (1.40 ml, 0.01 mol) was added, followed by the powdered salt (16) (0.79 g, 4.79 mmol).
  • TNF levels in serum were assayed for TNF using a commercially available ELISA kit (OpEIA murine TNF kit, PharMingen, San Diego, CA, USA), according to the manufacturer's instructions. Briefly, samples (100 ⁇ l/well) in duplicate together with a serial dilution of TNF (31.25 - 2000 pg/ml) for the standard curve, were added to flat-bottom 96-well plates pre-coated with immobilised monoclonal anti-TNF antibody and incubated at room temperature for 2 h.
  • FCGI FCGI-containing phosphate buffer
  • DMSO dimethyl sulfoxide
  • phosphate buffer pH-containing phosphate buffer
  • pHs 3.0, 7.0 and 8.0
  • FCGI phosphate buffer
  • Aliquots 100 ⁇ l were automatically loaded onto a Agilent 1100 chromatogragh (Aigilent Technologies, Waldbronn, Germany). Compounds were separated by reversed phase chromatography with UV detection at 240 and 270nm.
  • the chromatography column used was a Luna 5 ⁇ phenylhexyl (100mm x 4.6mm) and the mobile phase consisted of solvent A: acetonitrile in water (80%v/v) and solvent B: ammonium formate buffer (45mM; ph 3.5) at 0.6ml/min.
  • a linear gradient was used to separate FCGI and the internal standard, phenacetin.
  • the mobile phase conditions were: 95% solvent B (0-25min), changing to 100% solvent A over 25-30 min, returning to 95% solvent B over 30-35min.
  • FCGI was found to be completely stable over 24 hours at pH 3.0, but unstable at pH 8.0 ( Figure 3).
  • Example 7 Inhibition ofangiogenesis in vifto
  • ECV304 human endothelial-like cells (from ATCC, CRL-1998) were plated at a concentration of IxIO 5 in a final volume of ImI of M- 199 medium supplemented with 10% FBS, containing FCGI, CGI and 19a at varying concentrations (2 - 500 ⁇ g/ml) and was plated onto the solidified matrigel matrix (100 ⁇ l, diluted 1:3, Becton Dickinson, Bedford, USA) in 24-well plates and incubated at 37 0 C, 5% CO 2 . Development of capillary-like networks was evaluated 18 hours after plating. The plates were photographed using 5.0 megapixel professional digital compact camera (Olympus Camedia c-5050 zoom).
  • the analogues were tested for their ability to inhibit the production of IL-6, a growth factor required by multiple myeloma cells to survive.
  • RPMI 8226 from ATCC, CCL-1555
  • human multiple myeloma cells (10 per well) were cultured with lipopolysaccharide (0.1 ⁇ g/ml) and varying concentrations of each analogue in RPMI medium supplemented with 10% FBS in 96-well plates for 20 hours. Culture supernatants were assayed for IL-6 concentrations using ELISA kit for human IL-6

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Abstract

La présente invention concerne certains dérivés de l'acide benzoïque et l'utilisation de ceux-ci dans le traitement de troubles néoplasiques et en tant qu'immunomodulateurs. En particulier la présente invention concerne des analogues de l'acide carboxybenzoylglutamique et l'utilisation de ceux-ci.
PCT/NZ2007/000178 2006-07-12 2007-07-12 Dérivés de l'acide benzoïque ayant des propriétés immunomodulatrices et anticancéreuses WO2008007979A1 (fr)

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US8314107B2 (en) 2008-04-23 2012-11-20 Rigel Pharmaceuticals, Inc. Carboxamide compounds and methods for using the same
CN103787956A (zh) * 2014-01-20 2014-05-14 上海医药工业研究院 用于制备泊马度胺的中间体的制备方法
WO2019043214A1 (fr) 2017-09-04 2019-03-07 F. Hoffmann-La Roche Ag Glutarimide
WO2021105334A1 (fr) * 2019-11-27 2021-06-03 Captor Therapeutics S.A. Dérivés de pipéridine-2,6-dione qui se lient au céréblon, et leurs procédés d'utilisation
CN113166100A (zh) * 2018-06-29 2021-07-23 达纳-法伯癌症研究所有限公司 免疫调节性化合物
CN116655595A (zh) * 2023-06-05 2023-08-29 中国人民解放军军事科学院军事医学研究院 2,6-哌啶二酮衍生物及其制备和用途

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Cited By (17)

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Publication number Priority date Publication date Assignee Title
US8314107B2 (en) 2008-04-23 2012-11-20 Rigel Pharmaceuticals, Inc. Carboxamide compounds and methods for using the same
US8785449B2 (en) 2008-04-23 2014-07-22 Rigel Pharmaceuticals, Inc. Carboxamide compounds and methods for using the same
US8871770B2 (en) 2008-04-23 2014-10-28 Rigel Pharmaceuticals Inc. Carboxamide compounds and methods for using the same
US9062052B2 (en) 2008-04-23 2015-06-23 Rigel Pharmaceuticals, Inc. Carboxamide compounds and methods for using the same
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