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WO2001034585A1 - Derives de semicarbazone et leur utilisation en tant que mimetiques de la thrombopoietine - Google Patents

Derives de semicarbazone et leur utilisation en tant que mimetiques de la thrombopoietine Download PDF

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Publication number
WO2001034585A1
WO2001034585A1 PCT/US2000/030383 US0030383W WO0134585A1 WO 2001034585 A1 WO2001034585 A1 WO 2001034585A1 US 0030383 W US0030383 W US 0030383W WO 0134585 A1 WO0134585 A1 WO 0134585A1
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WIPO (PCT)
Prior art keywords
substituted
hydroxy
aryl
amino
compound
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PCT/US2000/030383
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English (en)
Inventor
Juan I. Luengo
Kevin J. Duffy
Antony Shaw
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Smithkline Beecham Corporation
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Filing date
Publication date
Application filed by Smithkline Beecham Corporation filed Critical Smithkline Beecham Corporation
Priority to US10/129,211 priority Critical patent/US6720345B1/en
Priority to EP00976915A priority patent/EP1228051A1/fr
Priority to AU14622/01A priority patent/AU1462201A/en
Priority to JP2001536532A priority patent/JP2003513965A/ja
Publication of WO2001034585A1 publication Critical patent/WO2001034585A1/fr

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    • 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole 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
    • C07D277/36—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • TPO thrombopoietin
  • Megakaryocytes are bone marrow-derived cells, which are responsible for producing circulating blood platelets. Although comprising ⁇ 0.25% of the bone marrow cells in most species, they have >10 times the volume of typical marrow cells. See Kuter et al. Proc. Natl. Acad. Aci. USA 91 : 11104-11108 (1994). Megakaryocytes undergo a process known as endomitosis whereby they replicate their nuclei but fail to undergo cell division and thereby give rise to polypoid cells. In response to a decreased platelet count, the endomitotic rate increases, higher ploidy megakaryocytes are formed, and the number of megakaryocytes may increase up to 3-fold.
  • TPO thrombopoietin
  • TPO has been shown in several studies to increase platelet counts, increase platelet size, and increase isotope incorporation into platelets of recipient animals. Specifically, TPO is thought to affect megakaryocytopoiesis in several ways: (1) it produces increases in megakaryocyte size and number; (2) it produces an increase in DNA content, in the form of polyploidy, in megakaryocytes; (3) it increases megakaryocyte endomitosis; (4) it produces increased maturation of megakaryocytes; and (5) it produces an increase in the percentage of precursor cells, in the form of small acetylcholinesterase-positive cells, in the bone marrow.
  • TPO has potential useful application in both the diagnosis and the treatment of various hematological disorders, for example, diseases primarily due to platelet defects. Ongoing clinical trials with TPO have indicated that TPO can be administered safely to patients. In addition, recent studies have provided a basis for the projection of efficacy of TPO therapy in the treatment of thrombocytopenia, and particularly thrombocytopenia resulting from chemotherapy, radiation therapy, or bone marrow transplantation as treatment for cancer or lymphoma. See e.g., McDonald (1992) Am. J. Ped. Hematology/Oncoiogy 14: 8-21 (1992). The gene encoding TPO has been cloned and characterized. See Kuter et al.,
  • Thrombopoietin is a glycoprotein with two distinct regions separated by a potential Arg-Arg cleavage site.
  • the amino-terminal region is highly conserved in man and mouse, and has some homology with erythropoietin and interferon-alpha and interferon-beta.
  • the carboxy- terminal region shows wide species divergence.
  • TPO- R human TPO receptor
  • c-mpl human TPO receptor
  • TPO-R is a member of the haematopoietin growth factor receptor family, a family characterized by a common structural design of the extracellular domain, including for conserved C residues in the N-terminal portion and a WSXWS motif close to the transmembrane region. See Bazan Proc. Natl. Acad. Sci. USA 87: 6934-6938 (1990).
  • TPO-R as a key regulator of megakaryopoiesis is the fact that exposure of CD34 + cells to synthetic oligonucleotides antisense to TPO-R RNA significantly inhibits the appearance of megakaryocyte colonies without affecting erythroid or myeloid colony formation.
  • R! and R ⁇ are each independently selected from hydrogen, C ⁇ _ j 2alkyl, aryl, substituted aryl, and alkyl substituted with one or more substituents selected from the group consisting of: alkoxy, acyloxy, aryl, substituted aryl, amino, N- acylamino, oxo, hydroxy, cycloalkyl, substituted cycloalkyl, -C(0)OR ⁇ , - S(0)2NR 7 R 8 , -S(0) n R 6 , aryloxy, nitro, cyano, halogen, and protected -OH, where
  • R" is selected from hydrogen, alkyl, cycloalkyl, Cj-C ⁇ aryl, substituted alkyl, substituted cycloalkyl and substituted Cj-C ⁇ aryl
  • R ' and R° are independently selected from hydrogen, cycloalkyl, aryl, substituted cycloalkyl, substituted aryl, alkyl or alkyl substituted with one or more substituents selected from the group consisting of: alkoxy, acyloxy, aryloxy, amino, N-acylamino, oxo, hydroxy, -C(0)OR", -S(0) n R", - C(0)NR 6 R 6 , -S(0)2NR 6 R 6 , nitro, cyano, cycloalkyl, substituted cycloalkyl, halogen, C j -C ⁇ aryl, substituted Cj-C ⁇ aryl and protected -OH where R" is as described above; and
  • n 0-3; or R ⁇ and R- ⁇ taken together with the N group to which they are attached rmula (A):
  • Z is a bond or selected from S or NR->, where R-> is Cj-C ⁇ aryl or substituted C ⁇ - C 1 aryl;
  • R 3 is selected from hydrogen, Cj-Cjoalkyl, phenyl, substituted phenyl, carboxyl or C ] -C ⁇ ⁇ alkoxycarbonyl ;
  • L is a group of formula (L):
  • A, B, D and E independently represent CR ⁇ 1 or N; where R ⁇ 1 is selected from hydrogen, halogen, -CF 3 , -CN, -SO3H, -S0 3 Na, -S0 2 R 14 , -N0 2 , phenyl, substituted phenyl, Cj-CjQalkyl, Ci -Cjoalkoxy, arylalkoxy, - COR 14 , -NR 12 R 13 , hydroxy or cycloalkyl; where R 14 is selected from hydroxy, Cj-CiQalkyl, phenyl, amino, mono- or dialkylamino; Rl2 and R 13 are independently selected from hydrogen, Ci .
  • Y is selected from -S, -O and -NR*- ⁇ where R*5 is selected from hydrogen, C j -
  • X is selected from -SR 16 , -OR 16 or -NHR 17 ; where R 16 is hydrogen, C j -C j ⁇ alkyl or substituted C]-C ⁇ o a lkyl; R* ' is hydrogen, Cj-CjQalkyl, substituted Ci -Ci ⁇ alkyl, C j -C ⁇ alkylphenyl, C ⁇ - Cj Q acyl, substituted C ⁇ -C ⁇ r)&cy ⁇ or S ⁇ 2R ⁇ ; where R ⁇ is C ⁇ -C ]Q alkyl, substituted Cj-Cjoalkyl, Cj-C ⁇ aryl or substituted Cj-C ⁇ aryl; and pharmaceutically acceptable salts, hydrates, solvates and esters thereof,
  • R ⁇ is not a substituted or unsubstituted pyridyl or a substituted or unsubstituted phenyl.
  • This invention relates to a method of treating thrombocytopenia, which comprises administering to a subject in need thereof an effective amount of a TPO mimetic compound of Formula (I).
  • the present invention also relates to the discovery that the compounds of Formula (I) are active as agonists of the TPO receptor.
  • compositions comprising a pharmaceutical carrier and compounds useful in the methods of the invention.
  • Also included in the present invention are methods of co-administering the presently invented TPO mimetic compounds with further active ingredients.
  • This invention relates to compounds of Formula (I) as described above.
  • Preferred among the presently invented Formula I compounds are those in which R5 is Cj-C ⁇ aryl substituted with a carboxy or sulfonic acid substituent.
  • R! and R 2 are selected from hydrogen, Ci . j oalkyl, benzyl, substituted benzyl,
  • Z is S or -NR ⁇ where R ⁇ is phenyl substituted with a carboxy or sulfonic acid substituent, a six membered aromatic ring containing from 1 to 3 heteroatoms and substituted with a carboxy or sulfonic acid substituent, or a C j -
  • L is C -Cgaryl optionally substituted with form 1 to 3 substituents selected from the group consisting of: Br, Cl, CF3, F, -CH3 and substituted phenyl;
  • Y is S
  • X is -OH
  • R-> is not a substituted or unsubstituted pyridyl or a substituted or unsubstituted phenyl.
  • Preferred among the presently invented compounds are: -[(2-hydroxy-3,5-dibromophen-l-yl)methyleneamino]-2-thioxothiazolidin-4-one (Compound A); -(3-carboxyphenyl)-l-[(l-(3,4-dimethylphenyl)-5-hydroxy-3-methyl-lH-pyrazol-4- ylmethylene)amino]-2-thioxoimidazolidin-4-one; 3-(4-carboxyphenyl)-l-[( l-(3,4-dimethylphenyl)-5-hydroxy-3-methyl-lH-pyrazol-4- ylmethylene)amino]-2-thioxoimidazolidin-4-one; 5-(4-carboxybenzylidene)-3-[( 1 - ⁇ 3,4-dimethylphenyl ⁇ -4-hydroxy-3-methyl- lH-pyrazol-4- ylmethylene)amino
  • Compounds of Formula (I) are included in the pharmaceutical compositions of the invention and used in the methods of the invention.
  • protected hydroxy or “protected -O ⁇ ” as used herein, is meant the alcoholic or carboxylic-O ⁇ groups which can be protected by conventional blocking groups in the art as described in "Protective Groups In Organic Synthesis” by Theodora W. Greene, Wiley-Interscience, 1981, New York. Compounds containing protected hydroxy groups may also be useful as intermediates in the preparation of the pharmaceutically active compounds of the invention.
  • aryl as used herein, unless otherwise defined, is meant a cyclic or polycyclic aromatic ring containing from 1 to 14 carbon atoms and optionally containing from one to five heteroatoms, provided that when the number of carbon atoms is 1 the aromatic ring contains at least four heteroatoms, when the number of carbon atoms is 2 the aromatic ring contains at least three heteroatoms, when the number of carbons is 3 the aromatic ring contains at least two heteroatoms and when the number of carbon atoms is 4 the aromatic ring contains at least one heteroatom.
  • Ci -C ⁇ aryl as used herein, unless otherwise defined, is meant phenyl, naphthalene, 3,4-methylenedioxyphenyl, pyridine, biphenyl, quinoline, pyrimidine, quinazoline, thiophene, furan, pyrrole, pyrazole, imidazole and tetrazole.
  • ' ⁇ -Cgaryl as used herein, unless otherwise defined, is meant a cyclic or polycyclic aromatic ring containing from 3 to 6 carbon atoms and optionally containing from one to 4 heteroatoms, provided that when the number of carbon atoms is 3 the aromatic ring contains at least two heteroatoms and when the number of carbon atoms is 4 the aromatic ring contains at least one heteroatom.
  • substituted as used herein, unless otherwise defined, is meant that the subject chemical moiety has one or more substituents selected from the group consisting of: hydroxyalkyl, alkoxy, acyloxy, alkyl, aryl, amino, N-acylamino, hydroxy, -(C ⁇ 2) ⁇ C(0)OR 6 , -S(0) n R 7 , nitro, cyano, halogen, trifluoromethyl and protected -OH, where g is 0-6, R ⁇ is hydrogen or alkyl, n is 0-3, and R ' is hydrogen or alkyl.
  • alkoxy as used herein is meant -Oalkyl where alkyl is as described herein including -OCH3 and -OC(CH 3 ) 2 CH 3 .
  • cycloalkyl as used herein unless otherwise defined, is meant a nonaromatic, unsaturated or saturated, cyclic or polycyclic C3-C12.
  • cycloalkyl and substituted cycloalkyl substituents as used herein include: cyclohexyl, 4-hydroxy-cyclohexyl, 2-ethylcyclohexyl, propyl 4- methoxycyclohexyl, 4-methoxycyclohexyl, 4-carboxycyclohexyl and cyclopentyl.
  • acyloxy as used herein is meant -OC(0)alkyl where alkyl is as described herein.
  • Examples of acyloxy substituents as used herein include: -OC(0)CH3, - OC(0)CH(CH 3 ) 2 and -OC(0)(CH 2 )3CH 3 .
  • N-acylamino as used herein is meant -N(H)C(0)alkyl, where alkyl is as described herein.
  • Examples of N-acylamino substituents as used herein include: - N(H)C(0)CH 3 , -N(H)C(0)CH(CH 3 ) 2 and -N(H)C(0)(CH 2 ) 3 CH 3 .
  • aryloxy as used herein is meant -OC ⁇ -C ⁇ aryl where Cg-C ⁇ ryl is phenyl, naphthyl, 3,4-methylenedioxyphenyl, pyridyl or biphenyl optionally substituted with one or more substituents selected from the group consisting of: alkyl, hydroxyalkyl, alkoxy, trifuloromethyl, acyloxy, amino, N-acylamino, hydroxy, -(CH2) C(0)OR ⁇ , - S(0) n R 7 , nitro, cyano, halogen and protected -OH, where g is 0-6, R" is hydrogen or alkyl, n is 0-3 and R 7 is hydrogen or alkyl.
  • substituents as used herein include: phenoxy, 4-fluorophenyloxy and biphenyloxy.
  • heteroatom oxygen, nitrogen or sulfur.
  • halogen as used herein is meant a substituent selected from bromide, iodide, chloride and fluoride.
  • alkyl and derivatives thereof and in all carbon chains as used herein is meant a linear or branched, saturated or unsaturated hydrocarbon chain having C ] -Ci2 carbon atoms.
  • treating and derivatives thereof as used herein, is meant prophylatic or therapeutic therapy.
  • esters can be employed, for example methyl, ethyl, pivaloyloxymethyl, and the like for -COOH, and acetate maleate and the like for -OH, and those esters known in the art for modifying solubility or hydrolysis characteristics for use as sustained release or prodrug formulations.
  • novel compounds of Formula I are prepared as shown in Scheme I below wherein R 1 , R 2 , R , Z, Y, L and X are as defined in Formula I and provided that these substituents do not include any such substituents that render inoperative the Scheme I process. All of the starting materials are commercially available or are readily made from commercially available starting materials by those of skill in the art.
  • the treatment of thrombocytopenia is accomplished by enhancing the production of platelets.
  • co-administering and derivatives thereof as used herein is meant either simultaneous administration or any manner of separate sequential administration of a TPO mimetic compound, as described herein, and a further active ingredient or ingredients, known to treat thrombocytopenia, including chemotherapy-induced thrombocytopenia and bone marrow transplantation and other conditions with depressed platelet production.
  • the compounds are administered in a close time proximity to each other.
  • the compounds are administered in the same dosage form, e.g. one compound may be administered topically and another compound may be administered orally.
  • the pharmaceutically active compounds of the present invention are active as TPO mimetics they exhibit therapeutic utility in treating thrombocytopenia and other conditions with depressed platelet production.
  • the murine BaF3 cells express TPO receptors and closely match the pattern of STAT (signal transducers and activators of transcription) activation observed in primary murine and human bone marrow cells in response to TPO.
  • STAT signal transducers and activators of transcription
  • Some of the preferred compounds of this invention were also active in an in vitro proliferation assay using the murine 32D-mpl cell line (Bartley, T. D. et al., Cell, 1994, 77, 1117-1124).
  • 32D-mpl cells express Tpo-R and their survival is dependent on the presence of TPO.
  • compositions within the scope of this invention are useful as TPO mimetics in mammals, including humans, in need thereof.
  • Compound A showed activation of about 9% of control (control is the maximal response to TPO) at a concentration of 10 uM in the luciferase assay.
  • Some of the preferred compounds within the scope of the invention showed activation from about 0% to 9% control at a concentration of 1-10 uM in the luciferase assay.
  • the preferred compounds of the invention also promoted the proliferation of 32D- mpl cells at a concentration of 10 to 30 uM.
  • the present invention therefor provides a method of treating thrombocytopenia and other conditions with depressed platelet production, which comprises administering a compound of Formula (I), and pharmaceutically acceptable salts, hydrates, solvates and esters thereof in a quantity effective to enhance platelet production.
  • the compounds of Formula (I) also provide for a method of treating the above indicated disease states because of their demonstrated ability to act as TPO mimetics.
  • the drug may be administered to a patient in need thereof by any conventional route of administration, including, but not limited to, intravenous, intramuscular, oral, subcutaneous, intradermal, and parenteral.
  • Solid or liquid pharmaceutical carriers are employed.
  • Solid carriers include, starch, lactose, calcium sulfate dihydrate, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid.
  • Liquid carriers include syrup, peanut oil, olive oil, saline, and water.
  • the carrier or diluent may include any prolonged release material, such as glyceryl monostearate or glyceryl distearate, alone or with a wax.
  • the amount of solid carrier varies widely but, preferably, will be from about 25 mg to about 1 g per dosage unit.
  • the preparation will be in the form of a syrup, elixir, emulsion, soft gelatin capsule, sterile injectable liquid such as an ampoule, or an aqueous or nonaqueous liquid suspension.
  • the pharmaceutical preparations are made following conventional techniques of a pharmaceutical chemist involving mixing, granulating, and compressing, when necessary, for tablet forms, or mixing, filling and dissolving the ingredients, as appropriate, to give the desired oral or parenteral products.
  • Doses of the presently invented pharmaceutically active compounds in a pharmaceutical dosage unit as described above will be an efficacious, nontoxic quantity preferably selected from the range of 0.001 - 100 mg/kg of active compound, preferably 0.001 - 50 mg/kg.
  • the selected dose is administered preferably from 1-6 times daily, orally or parenterally.
  • Preferred forms of parenteral administration include topically, rectally, transdermally, by injection and continuously by infusion.
  • Oral dosage units for human administration preferably contain from 0.05 to 3500 mg of active compound. Oral administration, which uses lower dosages is preferred. Parenteral administration, at high dosages, however, also can be used when safe and convenient for the patient.
  • Optimal dosages to be administered may be readily determined by those skilled in the art, and will vary with the particular TPO mimetic in use, the strength of the preparation, the mode of administration, and the advancement of the disease condition. Additional factors depending on the particular patient being treated will result in a need to adjust dosages, including patient age, weight, diet, and time of administration.
  • the method of this invention of inducing TPO mimetic activity in mammals, including humans comprises administering to a subject in need of such activity an effective TPO mimetic amount of a pharmaceutically active compound of the present invention.
  • the invention also provides for the use of a compound of Formula (I) in the manufacture of a medicament for use as a TPO mimetic.
  • the invention also provides for the use of a compound of Formula (I) in the manufacture of a medicament for use in therapy.
  • the invention also provides for the use of a compound of Formula (I) in the manufacture of a medicament for use in enhancing platelet production.
  • the invention also provides for the use of a compound of Formula (I) in the manufacture of a medicament for use in treating thrombocytopenia.
  • the invention also provides for a pharmaceutical composition for use as a TPO mimetic which comprises a compound of Formula (I) and a pharmaceutically acceptable carrier.
  • the invention also provides for a pharmaceutical composition for use in the treatment of thrombocytopenia which comprises a compound of Formula (I) and a pharmaceutically acceptable carrier.
  • the invention also provides for a pharmaceutical composition for use in enhancing platelet production which comprises a compound of Formula (I) and a pharmaceutically acceptable carrier.
  • the pharmaceutically active compounds of the present invention can be co-administered with further active ingredients, such as other compounds known to treat thrombocytopenia, including chemotherapy-induced thrombocytopenia and bone marrow transplantation and other conditions with depressed platelet production, or compounds known to have utility when used in combination with a TPO mimetic.
  • further active ingredients such as other compounds known to treat thrombocytopenia, including chemotherapy-induced thrombocytopenia and bone marrow transplantation and other conditions with depressed platelet production, or compounds known to have utility when used in combination with a TPO mimetic.
  • Ethyl hydrazinoacetate hydrochloride (155 mg, 1.00 mmol) was added to a stirred solution of 3-isothiocyanatobenzoic acid (179 mg, 1.00 mmol) and di-isopropylethylamine (523 uL, 3.00 mmol) in dichloromethane (4 mL). The mixture was stirred for 96h, evaporated under reduced pressure and partitioned between aqueous acetic acid and ethyl acetate. The organic extracts were washed with water, saturated aqueous sodium chloride, dried (magnesium sulfate) and evaporated under reduced pressure.
  • An oral dosage form for administering a presently invented agonist of the TPO receptor is produced by filing a standard two piece hard gelatin capsule with the ingredients in the proportions shown in Table I, below.
  • Example 7 Injectable Parenteral Composition
  • An injectable form for administering a presently invented agonist of the TPO receptor is produced by stirring 1.5% by weight of 3-[(2-hydroxy-3,5-dibromophen-l- yl)methyleneamino]-2-thioxothiazolidin-4-one (Compound A), monosodium salt (Compound 2) in 10% by volume propylene glycol in water.
  • sucrose, calcium sulfate dihydrate and a presently invented agonist of the TPO receptor are mixed and granulated in the proportions shown with a 10% gelatin solution.
  • the wet granules are screened, dried, mixed with the starch, talc and stearic acid, screened and compressed into a tablet.

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Abstract

L'invention concerne des composés représentés par la formule (I), notamment un composé représenté par la formule (Ia). Ces composés sont des mimétiques non peptidiques de TPO utiles dans le traitement de la thrombocytopénie.
PCT/US2000/030383 1999-11-05 2000-11-03 Derives de semicarbazone et leur utilisation en tant que mimetiques de la thrombopoietine WO2001034585A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
US10/129,211 US6720345B1 (en) 1999-11-05 2000-11-03 Semicarbazone derivatives and their use as thrombopoietin mimetics
EP00976915A EP1228051A1 (fr) 1999-11-05 2000-11-03 Derives de semicarbazone et leur utilisation en tant que mimetiques de la thrombopoietine
AU14622/01A AU1462201A (en) 1999-11-05 2000-11-03 Semicarbazone derivatives and their use as thrombopoietin mimetics
JP2001536532A JP2003513965A (ja) 1999-11-05 2000-11-03 セミカルバゾン誘導体およびそれらのトロンボポエチン模倣物としての使用

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US16390799P 1999-11-05 1999-11-05
US60/163,907 1999-11-05

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WO2001034585A1 true WO2001034585A1 (fr) 2001-05-17

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Cited By (30)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002049413A2 (fr) * 2000-12-19 2002-06-27 Smithkline Beecham Corporation Mimetiques de thrombopoietine
WO2004033433A1 (fr) * 2002-10-09 2004-04-22 Nissan Chemical Industries, Ltd. Composes de pyrazolone et activateur du recepteur de la thrombopoietine
US6887890B2 (en) 2000-05-30 2005-05-03 Chugai Seiyaku Kabushiki Kaisha Compounds exhibiting thrombopoietin-like activities
WO2006062247A1 (fr) * 2004-12-08 2006-06-15 Nissan Chemical Industries, Ltd. Composé hétérocyclique substitué et activateur du récepteur de la thrombopoïétine
WO2006062249A1 (fr) * 2004-12-08 2006-06-15 Nissan Chemical Industries, Ltd. Composé hétérocyclique substitué et activateur du récepteur de la thrombopoïétine
US7160870B2 (en) 2000-05-25 2007-01-09 Smithkline Beecham Corporation Thrombopoietin mimetics
WO2007142308A1 (fr) 2006-06-07 2007-12-13 Nissan Chemical Industries, Ltd. Composé hétérocyclique azoté et activateur de récepteur de thrombopoïétine
US7351841B2 (en) 2003-06-06 2008-04-01 Nissan Chemical Industries, Ltd. Heterocyclic compounds and thrombopoietin receptor activators
US7521062B2 (en) 2002-12-27 2009-04-21 Novartis Vaccines & Diagnostics, Inc. Thiosemicarbazones as anti-virals and immunopotentiators
US7547719B2 (en) 2002-05-22 2009-06-16 Smithkline Beecham Corp. 3′-[(2z)-[1-(3,4-Dimethylphenyl)-1,5-dihydro-3-methyl-5-oxo-4h-pyrazol-4-ylidene]hy-drazino]-2′-hydroxy-[1,1′-piphenyl]-acid bis-(monoethanolamine)
WO2009092276A1 (fr) 2008-01-10 2009-07-30 Shanghai Hengrui Pharmaceutical Co., Ltd. Dérivés azoïques pyrazolone à substitution bicyclo, procédé de préparation et leur utilisation pharmaceutique
US7666857B2 (en) 2003-10-22 2010-02-23 Smithkline Beecham Corp. 2-(3,4-dimethylphenyl)-4-{[2-hydroxy-3′-(1h-tetrazol-5-yl)biphenyl-3-yl]-hydrazono}-5-methyl-2,4-dihydropyrazol-3-one choline
US7851503B2 (en) 2002-08-14 2010-12-14 Nissan Chemical Industries, Ltd. Thrombopoetin receptor activator and process for producing the same
US7960425B2 (en) 2005-07-20 2011-06-14 Nissan Chemical Industries, Ltd. Pyrazole compounds and thrombopoietin receptor activators
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