WO2009103218A1 - Dérivés d'hydrazine carboxamide d'éthylidène, processus de préparation et utilisation pharmaceutique de ceux-ci - Google Patents

Dérivés d'hydrazine carboxamide d'éthylidène, processus de préparation et utilisation pharmaceutique de ceux-ci Download PDF

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WO2009103218A1
WO2009103218A1 PCT/CN2009/000136 CN2009000136W WO2009103218A1 WO 2009103218 A1 WO2009103218 A1 WO 2009103218A1 CN 2009000136 W CN2009000136 W CN 2009000136W WO 2009103218 A1 WO2009103218 A1 WO 2009103218A1
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compound
ethyl
formula
mmol
group
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PCT/CN2009/000136
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WO2009103218A8 (fr
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邓炳初
吕贺军
陈一千
宋鹏
王胜蓝
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上海恒瑞医药有限公司
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Publication of WO2009103218A8 publication Critical patent/WO2009103218A8/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • C07D207/263—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C335/00—Thioureas, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C335/40—Thioureas, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of thiourea or isothiourea groups further bound to other hetero atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three 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, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D231/18—One oxygen or sulfur atom
    • C07D231/20—One oxygen atom attached in position 3 or 5
    • C07D231/22—One oxygen atom attached in position 3 or 5 with aryl radicals attached to ring nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
    • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D257/04—Five-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to a novel ethylene amide amide derivative of the formula (I), a process for the preparation thereof, and a pharmaceutical composition containing the same, and as a therapeutic agent, particularly as thrombopoietin (TPO) Mimetics and use as a thrombopoietin receptor agonist.
  • TPO thrombopoietin
  • TPO Thrombopoietin
  • MDF megakaryocyte growth and development factor
  • TEF thrombocytopoiesis stimulating factor
  • c-Mpl ⁇ ⁇ c -myeloproliferative leukemia ligand, c-Mpl
  • mpl ligand megapoietin
  • the activity of TPO is derived from the binding of TPO to the TPO receptor (also known as MPL).
  • TPO receptor also known as MPL.
  • the TPO receptor has been successfully cloned and the amino acid sequence has also been sequenced (Vigon et al., Proc. Nat. Acad. Sci., 89: 5640-5644 (1992)).
  • TPO is a 332-amino acid glycosylated polypeptide that plays a key role in regulating megakaryocyte production and platelet production by bone marrow megakaryocytes (Kuter et al., Proc. Nat. Acad. Sci. USA 91 : 11104 -11108 (1994); Barley et al., Cell 77: 1117-1124 (1994); Kaushansky et al., Nature 369: 568-571 (1994); Wendling et al” Nature 369: 571-574 (1994); And Sauvage et al., Nature 369: 533-538 (1994)).
  • TPO is produced in the liver but mainly acts on the bone marrow, stimulating the differentiation of stem cells into megakaryocytes and the proliferation of megakaryocytes, polyploidization, and most importantly, into platelets.
  • the body circulates and divides.
  • TPO is a major regulator of thrombocytopenia and a large number of platelet studies on increasing platelet count, size, and increased isotope in experimental animals (Metcalf, Nfltwre 369:519-520 (1994)).
  • megakaryocyte production is mainly affected by several ways: (1) causing an increase in the size and number of megakaryocytes; (2) increasing DNA inclusions, polyploid forms, megakaryocytes; (3) increasing the nuclear content of megakaryocytes Wired (4) Increase the number of mature megakaryocytes; (5) Increase the percentage of precursor cells, small acetylcholine enzyme-yang-sexual form of cells, bone marrow cells.
  • TPO has been used to diagnose and treat a variety of blood diseases, such as those caused primarily by platelet defects.
  • TP0 can be used to treat thrombocytopenia, especially chemotherapy, radiation and bone marrow transplantation for the treatment of cancer and lymphoma.
  • the thrombopoietin analog eltrombopag is reported by GSK in the patent (WO-00189457 / WO-01089457 / WO-2006064957) and exhibits considerable activity.
  • the present invention discloses a series of compounds that are more effective as TPO receptor agonists and are potent TPO mimetics. Summary of the invention
  • an object of the present invention to provide an ethylene amide amide derivative represented by the general formula (I), and their tautomers, enantiomers, and non-pairs.
  • R, R 2 or R 3 are each independently selected from a hydrogen atom or a fluorenyl group, or
  • R 2 with or R 3 and the atoms to which they are attached form a 4 to 6 membered ring;
  • R 5 is selected from a hydrogen atom or a fluorenyl group
  • X is selected from an oxygen atom or a sulfur atom
  • Y is 1 to 4 atomic spaces of one or more groups selected from a mercapto group or an aryl group, wherein the aryl group or alkyl group is optionally further further selected from one or more selected from halogen, decyl or aryl Substituted by a substituent.
  • Y is selected from
  • R 6 is selected from a hydrogen atom, a halogen, a fluorenyl group or an aryl group;
  • R 7 is selected from a hydrogen atom or a fluorenyl group.
  • the present invention provides a compound represented by the formula ( ⁇ ) or a pharmaceutically acceptable salt, hydrate or solvent compound thereof:
  • R. , R 2 or each independently selected from a hydrogen atom or a fluorenyl group
  • R 2 and R 3 and the atoms to which they are attached form a 4 to 6 membered ring;
  • R 5 is selected from a hydrogen atom or an alkyl group
  • R 6 is selected from a hydrogen atom, a halogen, a fluorenyl group or an aryl group;
  • X is selected from an oxygen atom or a sulfur atom.
  • the present invention provides a compound of the formula (III) or a pharmaceutically acceptable salt, hydrate or solvent compound thereof,
  • R, R 2 or R 3 are each independently selected from a hydrogen atom or an alkyl group, or are bonded to 1 or R 3 and a bonded atom to form a halogen, alkyl, tetrazolyl, carboxyl or carboxylate;
  • R 5 is selected from a hydrogen atom or a fluorenyl group;
  • R 7 is selected from a hydrogen atom or a fluorenyl group
  • X is selected from an oxygen atom or a sulfur atom.
  • Preferred compounds of the invention include, but are not limited to:
  • R4 is selected from the group consisting of halogen, decyl, tetrazolyl, carboxy or carboxylic acid ester;
  • R 5 is selected from a hydrogen atom or an alkyl group
  • X is selected from an oxygen atom or a sulfur atom.
  • the present invention provides a compound represented by the formula (IB) which is synthesized as a compound of the formula (I)
  • R 2 are independently selected from a hydrogen atom or an alkyl group, or
  • R 2 and R, or R 3 and the atoms to which they are attached form a 4 to 6 membered ring;
  • Y is 1 to 4 atomic spaces of one or more groups selected from a fluorenyl or aryl group, wherein the aryl or fluorenyl group is optionally further further selected from one or more selected from halogen, alkyl or aryl Substituted by a substituent.
  • Y is selected from
  • R 6 is selected from a hydrogen atom, a halogen, a fluorenyl group or an aryl group;
  • R 7 is selected from a hydrogen atom or an alkyl group.
  • a process for the preparation of a compound of the formula (; IA) which comprises the steps of: The substituted aniline is reacted with hydrazine, ⁇ '-deuterated carbonyl diimidazole, and the obtained compound is reacted with a hydrazine hydrate solution at room temperature to obtain a compound of the formula (I ⁇ ) wherein R 5 and X are as in the above formula (IA) Defined.
  • a process for the preparation of a compound of formula (IB) the process comprising the steps of:
  • the general formula (IB) and a compound X-substituted phenyl isocyanate under acidic conditions was heated to give compound of general formula (the I), wherein Ri, R2, R 3,, R 5, X and Y It is as defined in the above formula (I).
  • the invention relates to the use of a compound of formula (I) for the preparation of a TPO receptor agonist.
  • the invention relates to the use of a compound of formula (I) for the manufacture of a medicament for the treatment of thrombocytopenia. Further comprising a therapeutically effective amount of colony stimulating factor, a cytokine, a chemokine, an interleukin or a cytokine receptor agonist or antagonist, a soluble receptor, a receptor agonist, an antagonist antibody or with A combination of peptides or small molecules of the same mechanism.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I), and a pharmaceutically acceptable salt, hydrate or solvate thereof, and a pharmaceutically acceptable carrier.
  • the composition may further comprise a therapeutically effective amount of colony stimulating factor, cytokine, chemokine, leukocyte in combination Interleukin or cytokine receptor agonist.
  • Use of the composition in the manufacture of a medicament for treating thrombocytopenia.
  • the combined use includes the simultaneous or sequential use of the compounds described herein.
  • the present invention relates to a process for the preparation of a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and an effective amount of a compound of formula (I) and a pharmaceutically acceptable salt, hydrate or solvate thereof, which process comprises a formula (I)
  • the compound is combined with a pharmaceutically acceptable carrier and a diluent.
  • Alkyl means a saturated aliphatic hydrocarbon group comprising straight and branched chain groups of 1 to 20 carbon atoms.
  • fluorenyl groups having 1 to 10 carbon atoms such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, tert-butyl, pentyl and the like. More preferred are lower fluorenyl groups having 1 to 4 carbon atoms, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl or t-butyl groups and the like.
  • the alkyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more, independently selected from the group consisting of an alkyl group, a halogen, a hydroxyl group, a tetrazolyl group, an aryl group, a carboxylic acid or a carboxylic acid ester.
  • Aryl means a group having at least one aromatic ring structure, that is, an aromatic ring having a conjugated ⁇ -electron system, including a carbocyclic aryl group, a heteroaryl group, and a biaryl group.
  • the aryl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more, independently selected from an alkyl group, a halogen, a hydroxyl group, a tetrazolyl group, an aryl group, a heteroaryl group, a carboxylic acid or Carboxylic acid ester.
  • Halogen means fluoro, chloro, bromo or iodo.
  • tetrazolyl refers to a five-membered heteroaryl group containing four nitrogen atoms.
  • “Pharmaceutical composition” means a mixture of one or more of the compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, with other chemical components, such as a physiological/pharmaceutically acceptable carrier. And excipients.
  • the purpose of the pharmaceutical composition is to facilitate the administration of the compound to the organism.
  • the preparation method of the compound of the formula (I) or a salt thereof of the present invention comprises the following steps:
  • the substituted aniline is reacted with N,N'-X carbonyldiimidazole, and the obtained compound is reacted with a hydrazine hydrate solution at room temperature to obtain a compound of the formula ( ⁇ ⁇ ), or a substituted phenyl isocyanate and a hydrazine hydrate solution are reacted at room temperature.
  • a compound of the formula (I ⁇ ) is obtained by heating and condensing a compound of the formula dimethylaminoethylene and a compound of the formula (I ⁇ ) under acidic conditions.
  • the dimethylaminoethylidene derivative of the formula is reacted with a hydrazine hydrate solution at room temperature to obtain a compound of the formula (I ⁇ ); the compound of the formula (I ⁇ ) and the X-substituted phenylisocyanate are heated under acidic conditions. Condensation gives the compound of formula 1.
  • a compound of the formula (I ⁇ ) is reacted with a hydrazine hydrate solution at room temperature to obtain a compound of the formula (I ⁇ ); the compound of the formula (I ⁇ ) and the X-substituted phenylisocyanate are heated under acidic conditions. Condensation gives the compound of formula 1.
  • the structure of the compound is determined by nuclear magnetic resonance ('HNMR) or mass spectrometry (MS).
  • the 1H NMR shift ( ⁇ ) is given in parts per million (ppm).
  • the 1H NMR measurement was carried out using a Bruker AVANCE-400 nuclear magnetic apparatus, and the solvent was deuterated chloroform (CDC1 3 ), deuterated methanol (CD 3 OD), hexamethylene dimethyl sulfoxide (DMSO-
  • the internal standard is tetramethylsilane (TMS) and the chemical shift is given in units of l (T 6 (ppm);
  • the nitrogen atmosphere means that the reaction flask is connected to a nitrogen balloon of about 1 L volume;
  • the solution in the reaction means an aqueous solution
  • 1,3-dihydroindol-2-one lc (20 g, 150 mmol), m-bromo Toluene (30.78 g, 180 mmol), cuprous iodide (5.7 g, 30 mmol) and potassium carbonate (46 g, 330 mmol) were dissolved in 300 mL of acetonitrile, and ⁇ , ⁇ '-dimethyl-1 was added with stirring.
  • 2-Ethylenediamine (4 g, 45 mmol), heated to reflux for 2 h.
  • 1,3-Dihydroindole-2-one 2a (8.0 g, 60.1 mmol), 4-bromo-1,2-dimethylbenzene (13.4 g, 72.2 mmol), cuprous iodide (2.29 g, 12.0 mmol) And potassium carbonate (20.7 g, 150 mmol) was dissolved in 250 mL of acetonitrile, and hydrazine, ⁇ '-dimethyl-1,2-ethanediamine (1.59 g, 18 mmol) was added under stirring, and the mixture was refluxed for 2 hr.
  • Ethyl 4-isothiocyanate benzoate 2d (1.0 g, 4.83 mmol) was dissolved in 15 mL of absolute ethanol, and 50% hydrazine hydrate solution (2.4 mL, 24.13 mmol) and 20 mL absolute ethanol were added with stirring. Heat to reflux for 0.5 hours. The spot plate was traced until the starting material disappeared, cooled to room temperature, filtered, and the filter cake was dried under vacuum to give ethyl 4-(indolesulfonyl)benzoate 2e (1.l g, white solid). Yield: 95.7%.
  • the residue was purified by silica gel column chromatography eluting eluting eluting Yield: 13.7%.
  • Methyl 4-methylaminobenzoate 10c (100 mg, 0.605 mmol) and hydrazine, hydrazine, -thiocarbonyldiimidazole (162 Mg, 0.908 mmol) was dissolved in 15 mL of dichloromethane and allowed to react at room temperature for 4 days. The reaction was quenched by TLC to dryness eluting with silica gel elution elution elution elution elution elution elution elution Yield: 77.8%.
  • 2,3-Dihydro-1H-indole-5-amine 13a (11.73 g, 88.2 mmol) was dissolved in 50 mL of acetonitrile with stirring Hydrochloric acid (2N, 100 mL) was added. After cooling in ice-water bath, sodium nitrite (6.87 g, 99.6 mmol) was added. After 20 minutes, potassium iodide (31.3 g, 188.6 mmol) was added, and the mixture was cooled in an ice water bath, and the reaction was stirred overnight. TLC followed the reaction to the disappearance of the starting material, and the reaction mixture was extracted with n-hexane (150 mL ⁇ 2).
  • Methyl 4-isothiocyanate benzoate 20d (4 g, 19.3 mmol) was dissolved in 50 mL of ethanol, and a 50% hydrazine hydrate solution (3.86 mL, 38.6 mmol) was added and reacted at 80 ° C for 30 minutes. The reaction was quenched by TLC until the title material disappeared. The reaction mixture was cooled to room temperature, filtered, and the filter cake was washed with ethanol (5 mL) and dried under vacuum to give methyl 4-(sulfonylamino)benzoate 20e (4.0 g, white solid ). Yield: 86.9%.
  • 5-Aminoindan 21a (6 g, 45 mmol) was dissolved in hydrochloric acid (2N, 50 mL) under ice-water bath, and 15 mL of sodium nitrite solution (3.4 g, 50 mmol) was added dropwise with stirring, and stirred for 30 minutes.
  • stannous chloride dihydrate (30.6 g, 135 mmol) was dissolved in 20 mL of concentrated hydrochloric acid, and added to the above solution, and reacted at room temperature for 1 hour.
  • the pH was adjusted to 10 with sodium hydroxide solution (3N, 30 mL), EtOAc (EtOAc)EtOAc.
  • the solution was concentrated to 400 mL under reduced pressure.
  • Example 7 The TPO series of compounds (Example 7) was observed for activation of STAT3 in 32D-Mpl mouse prolymphocytes B cells transfected with TPO receptor Mpl in vitro. After treatment of the cells with different concentrations of the compound of Example 7 and TPO-EoA, the effect was evaluated by Western blot. It was found by experiment that the activity of Example 7 is comparable to that of TPO-EoA.
  • RPMI-1640 was purchased from Gibco BRL; fetal bovine serum was purchased from Hyclone; anti-STAT3 phosphorylated antibody was purchased from Cell signaling; anti-rabbit lgG secondary antibody, nitrocellulose membrane, and ECL detection kit were purchased from Amershan; Reagents were purchased from Sigma
  • the 32D-Mpl cells were treated with the compound of Example 7, and then, the cells were collected and lysed, and the proteins were fixed to the same amount. After denaturation of the protein, SDS-PAGE was performed, transferred to a nitrocellulose membrane, and hybridized with an anti-STAT3 phosphorylated antibody (an anti-rabbit IgG antibody (secondary antibody), and finally detected by an ECL kit, and the X-ray film was exposed. The size and density of the protein bands were evaluated for the degree of activation of STAT3 by the compound of Example 7.
  • mouse 1L-3 ( chemicon Catalog no.ILOl 5 )
  • TPO Huma Thrombopoietin R Mab
  • Plasmid construction According to the TPOR gene sequence ⁇ ij provided by Entrez Gene ID: 4325, Refseq: NM-005373, the purchased EX-B0010-M02 plasmid (FulenGen) utilizes QuikChange® Multi Site Directed
  • the Mutagenesis Kit (Stratagene) kit performs a 2-point mutation.
  • the multi-point mutation primer sequences are: g49 la: 5'-gggaacttcagatcagctgggaggagccg-3 ', g491 a anti sense:
  • BAF3-TPOR cell line A BaF3 cell line stably expressing a highly functional TPO receptor was constructed. The by expressing human after the 2-point mutant TPO receptor and screening gene neomycin the EX-B0010-M02 plasmid 25 ⁇ ⁇ transfected with wild-type BaF3 cells (1X10 7), transfection instruments as Electro Square Porator ECM830 (BTX Division of Genetronic, Inc. US), transfection conditions: 250V, 18ms. The BAF3-TPOR stable cell line was obtained by G418 (Gibco, US) screening. BAF3-TPOR in RPMI1640
  • Centrifuge the cells by centrifugation Take appropriate amount of cell suspension at 1000 rpm, centrifuge for 5 minutes, discard the supernatant, resuspend the cells with 10 mL of cell culture medium without IL3, centrifuge at lOOOOrpm for 5 minutes, discard the supernatant. ;
  • test compound powder into 10 mM stock solution in DMSO, and dilute it with RPM11640. Same concentration: 30 ⁇ , 10 ⁇ , 3 ⁇ , ⁇ ⁇ , 0.3 ⁇ , 0.1 ⁇ , 0.03 ⁇ , 0.01 ⁇ , 0.003 ⁇ , 0.001 ⁇ ;

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Abstract

L'invention concerne des dérivés d'hydrazide carboxamide d'éthylidène représentés par la formule (I) ou des sels, un hydrate ou un solvate pharmaceutiquement acceptables de ceux-ci, des procédés de préparation de ces dérivés, des compositions pharmaceutiques les contenants et leur utilisation comme agent thérapeutique, en particulier comme mimétiques de thrombopoïétine (TPO) et leur utilisation comme agonistes du récepteur de thrombopoïétine. Les définitions des substituants dans la formule (I) sont telles que présentées dans la description.
PCT/CN2009/000136 2008-02-21 2009-02-06 Dérivés d'hydrazine carboxamide d'éthylidène, processus de préparation et utilisation pharmaceutique de ceux-ci WO2009103218A1 (fr)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011049213A1 (fr) * 2009-10-23 2011-04-28 日産化学工業株式会社 Composés hétérocycles fusionnés et activateur du récepteur de la thrombopoïétine
WO2013074459A1 (fr) 2011-11-14 2013-05-23 Ligand Pharmaceuticals, Inc. Procédés et compositions associés au récepteur du facteur de stimulation des colonies de granulocytes
WO2014150252A1 (fr) * 2013-03-15 2014-09-25 Ligand Pharmaceuticals Incorporated Méthodes de traitement associées au récepteur du facteur de stimulation des colonies de granulocytes
CN104628647A (zh) * 2013-11-12 2015-05-20 上海医药工业研究院 3-甲基-1-(3,4-二甲基苯基)-2-吡唑啉-5-酮的制备方法

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US10736875B2 (en) 2011-11-14 2020-08-11 Ligand Pharmaceuticals, Inc. Methods and compositions associated with the granulocyte colony-stimulating factor receptor
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US9962370B2 (en) 2013-03-15 2018-05-08 Ligand Pharmaceuticals Incorporated Methods of treatment associated with the granulocyte colony-stimulating factor receptor
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