[go: up one dir, main page]
More Web Proxy on the site http://driver.im/

WO2001034585A1 - Semicarbazone derivatives and their use as thrombopoietin mimetics - Google Patents

Semicarbazone derivatives and their use as thrombopoietin mimetics Download PDF

Info

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
Authority
WO
WIPO (PCT)
Prior art keywords
substituted
hydroxy
aryl
amino
compound
Prior art date
Application number
PCT/US2000/030383
Other languages
French (fr)
Inventor
Juan I. Luengo
Kevin J. Duffy
Antony Shaw
Original Assignee
Smithkline Beecham Corporation
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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/en
Priority to AU14622/01A priority patent/AU1462201A/en
Priority to JP2001536532A priority patent/JP2003513965A/en
Publication of WO2001034585A1 publication Critical patent/WO2001034585A1/en

Links

Classifications

    • 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.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Hematology (AREA)
  • Diabetes (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Thiazole And Isothizaole Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

Compounds of formula (I), particularly a compound of formula (Ia), are non-peptide TPO mimetics, useful in the treatment of thrombocytopenia.

Description

SEMICARBAZONE DERIVATIVES AND THEIR USE AS TROMBOPOIETIN MIMETICS
FIELD OF THE INVENTION This invention relates to thrombopoietin (TPO ) mimetics and their use as promoters of thrombopoiesis and megakaryocytopoiesis.
BACKGROUND OF THE INVENTION 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. See Harker J. Clin. Invest. 47: 458-465 (1968). In contrast, in response to an elevated platelet count, the endomitotic rate decreases, lower ploidy megakaryocytes are formed, and the number of megakaryocytes may decrease by 50%. The exact physiological feedback mechanism by which the mass of circulating platelets regulates the endomitrotic rate and number of bone marrow megakaryocytes is not known. The circulating thrombopoietic factor involved in mediating this feedback loop is now thought to be thrombopoietin (TPO). More specifically, TPO has been shown to be the main humoral regulator in situations involving thrombocytopenia. See, e.g., Metcalf Nature 369:519-520 (1994). 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.
Because platelets (thrombocytes) are necessary for blood clotting and when their numbers are very low a patient is at risk of death from catastrophic hemorrhage, 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.,
Proc. Natl. 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). 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.
The DNA sequences and encoded peptide sequences for human TPO receptor (TPO- R; also known as c-mpl) have been described. See, Vigon et al. Proc. Natl. Acad. Sci. USA 89: 5640-5644 (1992). 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). Evidence that this receptor plays a functional role in hematopoiesis includes observations that its expression is restricted to spleen, bone marrow, or fetal liver in mice (see Souyri et al. Cell 63: 1137-1147 (1990)) and to megakaryocytes, platelets, and CD34+ cells in humans (see Methia et al. Blood 82: 1395-1401 (1993)). Further evidence for 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. Some workers postulate that the receptor functions as a homodimer, similar to the situation with the receptors for G-CSF and erythropoietin.
The slow recovery of platelet levels in patients suffering from thrombocytopenia is a serious problem, and has lent urgency to the search for a blood growth factor agonist able to accelerate platelet regeneration.
It would be desirable to provide compounds which allow for the treatment of thrombocytopenia by acting as a TPO mimetic.
As disclosed herein it has unexpectedly been discovered that certain substituted thiosemicarbazone derivatives are effective as agonists of the TPO receptor, they are potent TPO mimetics. SUMMARY OF THE INVENTION
Figure imgf000004_0001
wherein:
R! and R^ are each independently selected from hydrogen, Cι_j2alkyl, 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)2NR7R8, -S(0)nR6, 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, and 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)nR", - C(0)NR6R6, -S(0)2NR6R6, nitro, cyano, cycloalkyl, substituted cycloalkyl, halogen, Cj-C^aryl, substituted Cj-C^aryl and protected -OH where R" is as described above; and
n is 0-3; or R^ and R-^ taken together with the N group to which they are attached rmula (A):
Figure imgf000004_0002
(A) where R4 and R^ are each independently selected from two hydrogens, =NR , =0, =S, and =CHR-\ where R-> is Cj-C^aryl or substituted C j-C^aryl; and m is 0 to 2;
Z is a bond or selected from S or NR->, where R-> is Cj-C^aryl or substituted C\- C1 aryl;
R3 is selected from hydrogen, Cj-Cjoalkyl, phenyl, substituted phenyl, carboxyl or C ] -C \ øalkoxycarbonyl ;
L is a group of formula (L):
Figure imgf000005_0001
(L) where A, B, D and E independently represent CR^ 1 or N; where R^ 1 is selected from hydrogen, halogen, -CF3, -CN, -SO3H, -S03Na, -S02R14, -N02, phenyl, substituted phenyl, Cj-CjQalkyl, Ci -Cjoalkoxy,
Figure imgf000005_0002
arylalkoxy, - COR14, -NR12R13, hydroxy or cycloalkyl; where R14 is selected from hydroxy, Cj-CiQalkyl, phenyl, amino, mono- or dialkylamino; Rl2 and R13 are independently selected from hydrogen, Ci .jQalkyl, Cj-C^aryl, substituted Cj-C^aryl, Cι_ιoacyl or cycloalkyl; or either A=B or D=E alternatively represent O, S or NR12; where R12 is as defined above;
Y is selected from -S, -O and -NR*-\ where R*5 is selected from hydrogen, Cj-
CjQalkyl, substituted Cj-Cioalkyl, Cj-Cgalkylphenyl, substituted C\- Cgalkylphenyl, Cj-Cjoacyl, substituted Ci -C^oacyl, or Sθ2R^, where R^ is Cj- Cjoalkyl, substituted
Figure imgf000005_0003
and
X is selected from -SR16, -OR16 or -NHR17; where R16 is hydrogen, Cj-Cjøalkyl or substituted C]-Cιoalkyl; R* ' is hydrogen, Cj-CjQalkyl, substituted Ci -Ci øalkyl, Cj-Cβalkylphenyl, C\- CjQacyl, substituted C\-C\r)&cy\ or Sθ2R^; where R^ is Cι-C]Qalkyl, substituted Cj-Cjoalkyl, Cj-C^aryl or substituted Cj-C^aryl; and pharmaceutically acceptable salts, hydrates, solvates and esters thereof,
provided that;
when R! and R2 do not form a ring and X is not -NHS02R^, 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.
In a further aspect of the invention there is provided novel processes and novel intermediates useful in preparing the presently invented TPO mimetic compounds.
Included in the present invention are pharmaceutical 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.
DETAILED DESCRIPTION OF THE INVENTION
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.
Preferred among the presently invented Formula I compounds are those in which R! and R2 are selected from hydrogen, Ci .joalkyl, benzyl, substituted benzyl,
substituted phenyl, or R1 and R2 taken
Figure imgf000006_0001
are attached represent a ring of formula (A):
Figure imgf000007_0001
(A) where R4 and R1" are each independently selected from two hydrogens, =0, or =CHR-\ where R^ is Cj-C^aryl or substituted C]-Cj2aryl; and m is 0 to 2.
Preferred among the presently invented Formula I compounds are those in which:
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 Cj-
C2alkylphenyl substituted with a carboxy or sulfonic acid substituent;
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; and
X is -OH; and
pharmaceutically acceptable salts, hydrates, solvates and esters thereof,
provided that;
when R1 and R2 do not form a ring, 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]-2-thioxothiazolidin-4-one; and 5-(3-carboxybenzylidene)-3-[( l-{ 3,4-dimethylphenyl }-4-hydroxy-3-methyl-lH-pyrazol-4- ylmethylene)amino]-2-thioxothiazolidin-4-one.
Compounds of Formula (I) are included in the pharmaceutical compositions of the invention and used in the methods of the invention.
By the term "protected hydroxy" or "protected -OΗ" as used herein, is meant the alcoholic or carboxylic-OΗ 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.
By the term "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.
By the term "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.
By the term '^-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.
By the term "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, -(CΗ2)σC(0)OR6, -S(0)nR7, 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. By the term "alkoxy" as used herein is meant -Oalkyl where alkyl is as described herein including -OCH3 and -OC(CH3)2CH3.
The term "cycloalkyl" as used herein unless otherwise defined, is meant a nonaromatic, unsaturated or saturated, cyclic or polycyclic C3-C12. Examples of cycloalkyl and substituted cycloalkyl substituents as used herein include: cyclohexyl, 4-hydroxy-cyclohexyl, 2-ethylcyclohexyl, propyl 4- methoxycyclohexyl, 4-methoxycyclohexyl, 4-carboxycyclohexyl and cyclopentyl.
By the term "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(CH3)2 and -OC(0)(CH2)3CH3.
By the term "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)CH3, -N(H)C(0)CH(CH3)2 and -N(H)C(0)(CH2)3CH3.
By the term "aryloxy" as used herein is meant -OCβ-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)nR7, nitro, cyano, halogen and protected -OH, where g is 0-6, R" is hydrogen or alkyl, n is 0-3 and R7 is hydrogen or alkyl. Examples of aryloxy substituents as used herein include: phenoxy, 4-fluorophenyloxy and biphenyloxy.
By the term "heteroatom" as used herein is meant oxygen, nitrogen or sulfur.
By the term "halogen" as used herein is meant a substituent selected from bromide, iodide, chloride and fluoride.
By the term "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. Examples of alkyl substituents as used herein include: -CH3, -CH2-CH3, -CH2-CH2-CH3, -CH(CH3)2, -C(CH3)3, -(CH2)3-CH3, -CH2-CH(CH3)2 and -CH(CH3)- CH2-CH3, -CH=CH2.
By the term "treating" and derivatives thereof as used herein, is meant prophylatic or therapeutic therapy.
All publications, including but not limited to patents and patent applications, cited in this specification are herein incorporated by reference as though fully set forth.
Compounds of Formula (I) are included in the pharmaceutical compositions of the invention and used in the methods of the invention. Where a -COOH or -OH group is present, pharmaceutically acceptable 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.
The novel compounds of Formula I are prepared as shown in Scheme I below wherein R1 , R2, 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.
Scheme 1
Figure imgf000010_0001
<3>
Compounds X, are condensed with carbonyl compounds 2, available commercially or prepared by literature methods, in a suitable solvent with or without the addition of an acid catalyst such as HC1 to furnish the final compound 3.
The treatment of thrombocytopenia, as described herein, is accomplished by enhancing the production of platelets.
By the term "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. Preferably, if the administration is not simultaneous, the compounds are administered in a close time proximity to each other. Furthermore, it does not matter if the compounds are administered in the same dosage form, e.g. one compound may be administered topically and another compound may be administered orally.
Because 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.
In determining potency as TPO mimetics, the following assays were employed: Luciferase Assay
Compounds of the present invention were tested for potency as mimetics of the TPO receptor in a Luciferase assay such as described in Lamb, et al., Nucleic Acids Research 23: 3283-3289 (1995) and Seidel, et al., Proc. Natl. Acad. Sci.. USA 92: 3041- 3045 (1995) by substituting a TPO-responsive BaF3 cell line (Vigon et al. Proc. Natl. Acad. Sci. USA 1992, 89, 5640-5644) for the HepG2 cells utilized therein. 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. 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.
The pharmaceutically active compounds within the scope of this invention are useful as TPO mimetics in mammals, including humans, in need thereof.
Within the scope of the invention 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.
The pharmaceutically active compounds of the present invention are incorporated into convenient dosage forms such as capsules, tablets, or injectable preparations. 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. Similarly, 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. When a liquid carrier is used, 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. When treating a human patient in need of a TPO mimetic, 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.
No unacceptable toxicological effects are expected when compounds of the invention are administered in accordance with the present invention.
In addition, 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.
Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. The following Examples are, therefore, to be construed as merely illustrative and not a limitation of the scope of the present invention in any way.
Experimental Details
Example 1
3- r(2-hydroxy-3 ,5-dibromophen- 1 -yl)methyleneamino1-2-thioxothiazolidin-4-one
A solution of 3,5-dibromo-2-hydroxybenzaldehyde (104 mg, 0.371 mmol) in methanol (1 mL) was added to a solution of 3-aminorhodanine (50 mg, 0.337 mmol) in methanol (5 mL) and the mixture allowed to stand at room temperature. After 1 h, the precipitate was filtered, washed (methanol, ether) and dried to give the title compound (93 mg, 67%) as a pale yellow solid. LCMS m/e 409, 411, 413 [M+H]+.
Example 2
3-(3-carboxyphenyl)- 1 -IT l-(3,4-dimethylphenyl)-5-hvdroxy-3-methyl- lH-pyrazol-4- ylmethylene)amino1-2-thioxoimidazolidin-4-one
a) 1 -(3,4-Dimethylphenyl)-3-methyl-3-pyrazolin-5-one. A solution of 3,4-dimethylphenylhydrazine (7.3 g; 0.053 mol.) and ethyl acetoacetate (6.9 g; 0.053 mol.) in glacial acetic acid (50.0 mL) was stirred and heated at 100° for 24h. The solvent was evaporated and the product purified by chromatography (silica gel, 50% ethyl acetate/hexanes) to afford the title compound (16.8 g; 64%). MS(ES) m z 203 [M+H].
b) l-(3,4-Dimethylphenyl)-5-hydroxy-3-methyl-lH-pyrazole-4-carbaldehyde.
Phosphorus oxychloride (4.82 mL, 51.6 mmol) was added dropwise to an ice- cooled, stirred suspension of 1 -(3,4-dimethy lphenyl)-3-methyl-3-pyrazolin-5-one (8.70 g, 43.0 mmol) in dimethylformamide (18.0 mL) at such a rate as to maintain the temperature below 20 °C. After the addition, the mixture was heated at 100 °C for 2h, then cooled, poured into iced water (200 mL). The resulting mixture was stirred for 18h, then filtered. The solid was washed with water and dried to give the title compound (7.83 g, 79%) as a cream-coloured powder. MS (ES) m/e 231 [M+Ηf.
c) 3-(3-carboxyphenyl)- 1 - [( 1 -(3,4-dimethy Ipheny l)-5-hydroxy-3-methyl- 1 H-pyrazol-4- ylmethylene)amino]-2-thioxoimidazolidin-4-one.
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. The residue was chromatographed (silica gel, 5-15% methanol/ethyl acetate, then 20% methanol/ethyl acetate + 0.5% acetic acid) to give l-amino-3-(3-carboxyphenyl)-2-thioxoimidazolidin-4- one (50 mg, 51%) contaminated with 6% uncyclised by-product, suitable for the next step. A solution of l-amino-3-(3-carboxyphenyl)-2-thioxoimidazolidin-4-one (50 mg, 0.199 mmol) and l-(3,4-dimethylphenyl)-5-hydroxy-3-methyl-lH-pyrazole-4-carbaldehyde (55 mg, 0.239 mmol) in ethanol/methanol (2: 1, 15 mL) was allowed to stand a room temperature for 96 h. The solid was filtered off, washed with ether and dried to give the title compound (42 mg, 46%) as a powder. LCMS, m/e 464 [M+Η]+.
Example 3
3-(4-carboxyphenvD- 1 -\( 1 -(3,4-dimethy lphenyl)-5-hvdroxy-3-methyl- lH-pyrazol-4- ylmethylene)aminol-2-thioxoimidazolidin-4-one The procedure of example 2(c) was followed here using 4-isothiocyanatobenzoic acid instead of 3-isothiocyanatobenzoic acid to give the title compound as a powder. LCMS, m/e 464 [M+H]+.
Example 4
5-(4-carboxybenzylidene)-3- (l-{3,4-dimethylphenyl|-4-hydroxy-3-methyl-lH-pyrazol-4- ylmethylene)aminol-2-thioxothiazolidin-4-one
A mixture of 3-aminorhodanine (148 mg, 1.00 mmol), l-(3,4-dimethylphenyl)-5- hydroxy-3-methyl-lH-pyrazole-4-carbaldehyde (230 mg, 1.00 mmol) and ethanol (10 mL) was stirred 96 h. The solid was filtered, washed with ethanol and ether and dried. A mixture of the resulting crude imine (80 mg, 0.222 mmol), piperidine (2 mg, 0.022 mmol), 4-formylbenzoic acid (33 mg, 0.222 mmol), benzoic acid (3 mg, 0.022 mmol) and toluene (10 mL) was heated under reflux for 6 h in an apparatus fitted with a Dean and Stark separator to remove water. After cooling, the solid was filtered off, washed with toluene and ether, and purified by reverse phase ΗPLC (CombiPrep ODS-A, 10-90% acetonitrile/water + 0.1 % trifluoroacetic acid) to give the title compound (18 mg, 16%) as a solid. LCMS, m/e 493 [M+Η]+.
Example 5
5-(3-carboxybenzylidene)-3-rπ-{ 3,4-dimethylphenyl }-4-hydroxy-3-methyl-lH-pyrazol-4- ylmethylene)aminol-2-thioxothiazolidin-4-one
The procedure described in example 4 was followed here using 3-formylbenzoic acid instead of 4-formylbenzoic acid to give the title compound as a powder. LCMS, m e 493 [M+Η]+.
Example 6 - Capsule Composition
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.
Table I INGREDIENTS AMOUNTS
3-[(2-hydroxy-3,5-dibromophen-l-yl)methyleneamino]-2- 25 mg thioxothiazolidin-4-one (Compound A)
Lactose 55 mg
Talc 16 mg
Magnesium Stearate 4 mg
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.
Example 8 - Tablet Composition
The sucrose, calcium sulfate dihydrate and a presently invented agonist of the TPO receptor, as shown in Table II below, 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. Table II
INGREDIENTS AMOUNTS
3-[(2-hydroxy-3,5-dibromophen-l-yl)methyleneamino]-2- 20 mg thioxothiazolidin-4-one (Compound A) calcium sulfate dihydrate 30 mg sucrose 4 mg starch 2 mg talc 1 mg stearic acid 0.5 mg
While the preferred embodiments of the invention are illustrated by the above, it is to be understood that the invention is not limited to the precise instructions herein disclosed and that the right to all modifications coming within the scope of the following claims is reserved.

Claims

What is claimed is:
1. A method of treating of thrombocytopenia in a mammal, including a human, in need thereof which comprises administering to such mammal a therapeutically effective amount of a compound of Formula (I):
Figure imgf000017_0001
wherein:
R1 and X are each independently selected from hydrogen, Cj.^alkyl, 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)OR7, - S(0)2NR7R8, -S(0)nR6, aryloxy, nitro, cyano, halogen, and protected -OH, where R" is selected from hydrogen, alkyl, cycloalkyl,
Figure imgf000017_0002
substituted alkyl, substituted cycloalkyl and substituted Cj-C^aryl, and R7 and R8 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)nR", -
C(0)NR6R6, -S(0)2NR6R6, nitro, cyano, cycloalkyl, substituted cycloalkyl, halogen, Ci -C^aryl, substituted Cj-C^aryl and protected -OH where R° is as
Figure imgf000017_0003
attached rmula (A):
Figure imgf000017_0004
(A) where R4 and R1^ are each independently selected from two hydrogens, =NR^, =0, =S, and =CHR^, where R^ is Cj-C^aryl or substituted Ci -C^aryl; and m is 0 to 2;
Z is a bond or selected from S or NR-\ where R* is Cj-C^aryl or substituted Cj- C12aryl;
R-> is selected from hydrogen, Cj-Cjgalkyl, phenyl, substituted phenyl, carboxyl or Ci-Cjoalkoxycarbonyl;
L is a group of formula (L):
Figure imgf000018_0001
(L) where A, B, D and E independently represent CR1 1 or N; where R1 Ms selected from hydrogen, halogen, -CF3, -CN, -S0 H, -S03Na, -S02R14, -N02, phenyl, substituted phenyl, Cj-Cioalkyl, Cj-Cigalkoxy, Cj-Cioacyloxy, arylalkoxy, - COR14, -NR12R1 , hydroxy or cycloalkyl; where R 4 is selected from hydroxy, C]-CiQalkyl, phenyl, amino, mono- or dialkylamino;
R12 and R13 are independently selected from hydrogen, Ci.joalkyl, Cj-C^aryl, substituted Cj-C^aryl, Ci .jQacyl or cycloalkyl; or either A=B or D=E alternatively represent O, S or NR 2; where R12 is as defined above;
Y is selected from S, O and NR1^, where R1^ is selected from hydrogen, Cj- Cjgalkyl, substituted Ci -Cjo lkyl, C]-Cgalkylphenyl, substituted Cj- Cgalky Ipheny 1, Cj-Cjoacyl> substituted Cj-CiQacyl, or Sθ2R^, where R^ is Cj- Cigalkyl, substituted Cj-Cjoalkyl, Cj-C^aryl or substituted Cj-C^aryl; and
X is selected from SR16, OR16 or NHR17; where R16 is hydrogen, C^Cjøalkyl or substituted Cj-CjQalkyl; R17 is hydrogen, Cj -Cjoalkyl, substituted Cj-Cj Qalkyl, Cj-C5alkylphenyl, Cj- Cjøacyl, substituted Cj-Ci Qacyl or SO2R , where R" is Cj-Cj Qalkyl, substituted Cj-Cjøalkyl, Cj-C^aryl or substituted Ci-C^aryl; and
pharmaceutically acceptable salts, hydrates, solvates and esters thereof,
provided that;
when R1 and R2 do not form a ring and X is not -NHSU2R^, R^ is not a substituted or unsubstituted pyridyl or a substituted or unsubstituted phenyl.
2. The method of claim 1 wherein the compound is selected form: 3-[(2-hydroxy-3,5-dibromophen-l-yl)methyleneamino]-2-thioxothiazolidin-4-one; 3-(3-carboxyphenyl)- 1 -[( 1 -(3,4-dimethylphenyl)-5-hydroxy-3-methyl- lH-pyrazol-4- ylmethylene)amino]-2-thioxoimidazolidin-4-one;
3-(4-carboxypheny 1)- 1 - [( 1 -(3 ,4-dimethy lphenyl)-5-hydroxy-3-methy 1- 1 H-pyrazol-4- ylmethylene)amino]-2-thioxoimidazolidin-4-one; 5-(4-carboxybenzy lidene)-3- [( 1 - { 3,4-dimethylphenyl } -4-hydroxy-3-methyl- 1 H-pyrazol-4- ylmethylene)amino]-2-thioxothiazolidin-4-one; and 5-(3-carboxybenzy lidene)-3- [( 1 - { 3,4-dimethylphenyl } -4-hydroxy-3-methyl- lH-pyrazol-4-ylmethylene)amino]-2-thioxothiazolidin-4-one; or pharmaceutically acceptable salts, hydrates, solvates and esters thereof.
3. A method of enhancing platelet production in a mammal, including a human, in need thereof which comprises administering to such mammal a therapeutically effective amount of a compound of Claim 1.
4. The method of claim 3 wherein the compound is selected from: 3-[(2-hydroxy-3,5-dibromophen-l-yl)methyleneamino]-2-thioxothiazolidin-4-one; 3-(3-carboxyphenyl)- 1 - [( 1 -(3 ,4-dimethylpheny l)-5-hydroxy-3-methy 1- 1 H-pyrazol-4- ylmethylene)amino]-2-thioxoimidazolidin-4-one; 3-(4-carboxypheny 1)- 1 - [( 1 -(3 ,4-dimethy Ipheny l)-5-hydroxy-3-methy 1- lH-pyrazol-4- ylmethylene)amino]-2-thioxoimidazolidin-4-one; 5-(4-carboxybenzylidene)-3-[(l-{ 3,4-dimethylphenyl }-4-hydroxy-3-methyl-lH-pyrazol-4- ylmethylene)amino]-2-thioxothiazolidin-4-one; and
5-(3-carboxy benzy lidene)-3- [( 1 - { 3 ,4-dimethy Ipheny 1 } -4-hy droxy-3-methy 1- 1 H-pyrazol-4- ylmethylene)amino]-2-thioxothiazolidin-4-one; or pharmaceutically acceptable salts, hydrates, solvates and esters thereof.
5. A pharmaceutical composition for use in enhancing platelet production which comprises a compound of Claim 1 and a pharmaceutically acceptable carrier.
6. Use of a compound of Formula (I), as described in claim 1, in the manufacture of a medicament for use in treating of thrombocytopenia.
7. The method of claim 1 wherein the compound is administered orally.
8. The method of claim 1 wherein the compound is administered parenterally.
9. A method of agonizing the TPO receptor in a subject which comprises administering an effective amount of a compound of Formula (I), as described in claim
1.
10. A compound represented by Formula (I) as described in claim 1.
11. The method of claim 1 wherein the compound is
3-[(2-hydroxy-3,5-dibromophen-l-yl)methyleneamino]-2-thioxothiazolidin-4-one; or pharmaceutically acceptable salts, hydrates, solvates and esters thereof.
12. A compound of claim 10 selected from: 3-[(2-hydroxy-3,5-dibromophen-l-yl)methyleneamino]-2-thioxothiazolidin-4-one; 3-(3-carboxyphenyl)- 1 -[( 1 -(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-[(l-{ 3,4-dimethylphenyl }-4-hydroxy-3-methyl-lH-pyrazol-4- ylmethylene)amino]-2-thioxothiazolidin-4-one; and 5-(3-carboxybenzylidene)-3-[(l-{ 3,4-dimethylphenyl }-4-hydroxy-3-methyl-lH-pyrazol-4- ylmethylene)amino]-2-thioxothiazolidin-4-one; or a pharmaceutically acceptable salt, hydrate, solvate or ester thereof.
PCT/US2000/030383 1999-11-05 2000-11-03 Semicarbazone derivatives and their use as thrombopoietin mimetics WO2001034585A1 (en)

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 (en) 1999-11-05 2000-11-03 Semicarbazone derivatives and their use as thrombopoietin mimetics
AU14622/01A AU1462201A (en) 1999-11-05 2000-11-03 Semicarbazone derivatives and their use as thrombopoietin mimetics
JP2001536532A JP2003513965A (en) 1999-11-05 2000-11-03 Semicarbazone derivatives and their use as thrombopoietin mimetics

Applications Claiming Priority (2)

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

Publications (1)

Publication Number Publication Date
WO2001034585A1 true WO2001034585A1 (en) 2001-05-17

Family

ID=22592125

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2000/030383 WO2001034585A1 (en) 1999-11-05 2000-11-03 Semicarbazone derivatives and their use as thrombopoietin mimetics

Country Status (4)

Country Link
EP (1) EP1228051A1 (en)
JP (1) JP2003513965A (en)
AU (1) AU1462201A (en)
WO (1) WO2001034585A1 (en)

Cited By (30)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002049413A2 (en) * 2000-12-19 2002-06-27 Smithkline Beecham Corporation Thrombopoietin mimetics
WO2004033433A1 (en) * 2002-10-09 2004-04-22 Nissan Chemical Industries, Ltd. Pyrazolone compounds and thrombopoietin receptor activator
US6887890B2 (en) 2000-05-30 2005-05-03 Chugai Seiyaku Kabushiki Kaisha Compounds exhibiting thrombopoietin-like activities
WO2006062247A1 (en) * 2004-12-08 2006-06-15 Nissan Chemical Industries, Ltd. Substituted heterocyclic compound and thrombopoietin receptor activator
WO2006062249A1 (en) * 2004-12-08 2006-06-15 Nissan Chemical Industries, Ltd. Substituted heterocyclic compound and thrombopoietin receptor activator
US7160870B2 (en) 2000-05-25 2007-01-09 Smithkline Beecham Corporation Thrombopoietin mimetics
WO2007142308A1 (en) 2006-06-07 2007-12-13 Nissan Chemical Industries, Ltd. Nitrogen-containing heterocyclic compound and thrombopoietin receptor activator
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 (en) 2008-01-10 2009-07-30 Shanghai Hengrui Pharmaceutical Co., Ltd. Bicyclo-substituted pyrazolon azo derivatives, preparation process and pharmaceutical use thereof
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
US7968542B2 (en) 2005-07-15 2011-06-28 Nissan Chemical Industries, Ltd. Thiophene compounds and thrombopoietin receptor activators
US8026368B2 (en) 2005-11-07 2011-09-27 Nissan Chemical Industries, Ltd. Hydrazide compounds and thrombopoietin receptor activators
US8052994B2 (en) 2007-05-03 2011-11-08 Glaxosmithkline Llc 3′-[(2Z)-[1-(3,4-dimethylphenyl)-1,5-dihydro-3-methyl-5-oxo-4H-pyrazol-4-ylidene] hydrazino]-2′-hydroxy-[1,1′-biphenyl]-3-carboxylic acid bis-(monoethanolamine)
US8134013B2 (en) 2004-12-14 2012-03-13 Nissan Chemical Industries, Ltd. Amide compound and thrombopoietin receptor activator
WO2012102937A2 (en) 2011-01-25 2012-08-02 Irm Llc Compounds that expand hematopoietic stem cells
WO2013086436A1 (en) 2011-12-08 2013-06-13 Fred Hutchinson Cancer Research Center Compositions and methods for enhanced generation of hematopoietic stem/progenitor cells
WO2013110198A1 (en) 2012-01-27 2013-08-01 Université de Montréal Pyrimido[4,5-b]indole derivatives and use thereof in the expansion of hematopoietic stem cells
US8552031B2 (en) 2004-12-08 2013-10-08 Nissan Chemical Industries, Ltd. 3-ethylidenehydrazino substituted heterocyclic compounds as thrombopoietin receptor activators
US8609693B2 (en) 2009-05-29 2013-12-17 Glaxosmithkline Llc Methods of administration of thrombopoietin agonist compounds
US8642637B2 (en) 2009-06-11 2014-02-04 Jiangsu Hengrui Medicine Co., Ltd. Salts of bicyclo-substituted pyrazolon azo derivatives, preparation method and use thereof
US8895556B2 (en) 2007-12-26 2014-11-25 Critical Outcome Technologies Inc. Compounds and method for treatment of cancer
US8927281B2 (en) 2008-10-30 2015-01-06 Irm Llc Method for expanding hematopoietic stem cells
US8987272B2 (en) 2010-04-01 2015-03-24 Critical Outcome Technologies Inc. Compounds and method for treatment of HIV
US9284275B2 (en) 2007-01-11 2016-03-15 Critical Outcome Technologies Inc. Inhibitor compounds and cancer treatment methods
US10647718B2 (en) 2014-04-22 2020-05-12 Universitéde Montréal Compounds and use thereof in the expansion of hematopoietic stem cells and/or hematopoietic progenitor cells
US10724028B2 (en) 2014-10-31 2020-07-28 Nissan Chemical Industries, Ltd. Ligand-binding fiber and cell culture substrate using said fiber

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999011262A1 (en) * 1997-09-02 1999-03-11 Roche Diagnostics Gmbh Mpl-receptor ligands, process for their preparation, medicaments containing them and their use for the treatment and prevention of thrombocytopaenia and anaemia

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DD219485A1 (en) * 1983-11-17 1985-03-06 Rainer Beckert PROCESS FOR THE PREPARATION OF AZOMETHINES OF 1-AMINO-4,5-DIARYLIMINO-IMIDAZOLIDIN-2-THIONE

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999011262A1 (en) * 1997-09-02 1999-03-11 Roche Diagnostics Gmbh Mpl-receptor ligands, process for their preparation, medicaments containing them and their use for the treatment and prevention of thrombocytopaenia and anaemia

Non-Patent Citations (11)

* Cited by examiner, † Cited by third party
Title
BECKERT R ET AL: "Zur Reaktion von Derivaten des Thiosemicarbazids mit Bisimidchloriden der Oxalsäure", MONATSHEFTE FÜR CHEMIE, vol. 120, no. 12, December 1989 (1989-12-01), pages 1125 - 1137, XP002159340 *
BOLL. CHIM. FARM., vol. 137, no. 6, 1998, pages 210 - 217 *
DATABASE CROSSFIRE Beilstein Institut zur Foerderung der Chemischen Wissenschaften; XP002159341 *
DATABASE CROSSFIRE Beilstein Institut zur Foerderung der Chemischen Wissenschaften; XP002159342 *
DATABASE CROSSFIRE Beilstein Institut zur Foerderung der Chemischen Wissenschaften; XP002159343 *
DATABASE CROSSFIRE Beilstein Institut zur Foerderung der Chemischen Wissenschaften; XP002159344 *
DATABASE CROSSFIRE Beilstein Institut zur Foerderung der Chemischen Wissenschaften; XP002159345 *
FARM. ZH. (KIEV), vol. 23, no. 5, 1968, pages 40 - 44 *
KHIM. GETEROTSIKL. SOEDIN, vol. 7, 1971, pages 1182 - 1185 *
LIET. TSR MOKSLU AKAD. DARB. SER. B, 1973, pages 95,98 *
SB. NAUCHN. RAB., L'VOV. GOS. MED. INST., vol. 24, 1963, pages 22 *

Cited By (61)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7335649B2 (en) 2000-05-25 2008-02-26 Smithkline Beecham Corporation Thrombopoietin mimetics
US7674887B2 (en) 2000-05-25 2010-03-09 Glaxosmithkline Llc Thrombopoietin mimetics
US7473686B2 (en) 2000-05-25 2009-01-06 Smithkline Beecham Corp. Thrombopoietin mimetics
US7648971B2 (en) 2000-05-25 2010-01-19 Smithkline Beecham Corp. Thrombopoietin mimetics
US7452874B2 (en) 2000-05-25 2008-11-18 Smithkline Beecham Corp. Thrombopoietin mimetics
US7160870B2 (en) 2000-05-25 2007-01-09 Smithkline Beecham Corporation Thrombopoietin mimetics
US7439342B2 (en) 2000-05-25 2008-10-21 Smith Kline Beecham Corp. Thrombopoietin mimetics
US7790704B2 (en) 2000-05-25 2010-09-07 GlaxoSmithKline, LLC Thrombopoietin mimetics
US7332481B2 (en) 2000-05-25 2008-02-19 Smithkline Beecham Corporation Thrombopoietin mimetics
US6887890B2 (en) 2000-05-30 2005-05-03 Chugai Seiyaku Kabushiki Kaisha Compounds exhibiting thrombopoietin-like activities
WO2002049413A2 (en) * 2000-12-19 2002-06-27 Smithkline Beecham Corporation Thrombopoietin mimetics
US7241783B2 (en) 2000-12-19 2007-07-10 Smithkline Beecham Corporation Thrombopoietin mimetics
WO2002049413A3 (en) * 2000-12-19 2003-01-23 Smithkline Beecham Corp Thrombopoietin mimetics
US7795293B2 (en) 2002-05-22 2010-09-14 Glaxosmithkline Llc 3′-[(2Z)-[1-(3,4-dimethylphenyl)-1,5-dihydro-3-methyl-5-oxo-4H-pyrazol-4-ylidene]hydrazino]-2′-hydroxy-[1,1′-biphenyl]-3-carboxylic acid bis-(monoethanolamine)
US8846024B2 (en) 2002-05-22 2014-09-30 Glaxosmithkline Llc 3′-[(2Z)-[1-(3,4-dimethylphenyl)-1,5-dihydro-3-methyl-5-oxo-4H-pyrazol-4-ylidene]hydrazino]-2′-hydroxy-[1,1′-biphenyl]-3-carboxylic acid bis-(monoethanolamine)
US8088813B2 (en) 2002-05-22 2012-01-03 Glaxosmithkline Llc 3′-[(2Z)-[1-(3,4-dimethylphenyl)-1,5-dihydro-3-methyl-5-oxo-4H-pyrazol-4-ylidene]hydrazino]-2′-hydroxy-[1,1′-biphenyl]-3-carboxylic acid bis-(monoethanolamine)
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)
US7851503B2 (en) 2002-08-14 2010-12-14 Nissan Chemical Industries, Ltd. Thrombopoetin receptor activator and process for producing the same
WO2004033433A1 (en) * 2002-10-09 2004-04-22 Nissan Chemical Industries, Ltd. Pyrazolone compounds and thrombopoietin receptor activator
US8053453B2 (en) 2002-10-09 2011-11-08 Nissan Chemical Industries, Ltd. Pyrazolone compounds and thrombopoietin receptor activator
US7521062B2 (en) 2002-12-27 2009-04-21 Novartis Vaccines & Diagnostics, Inc. Thiosemicarbazones as anti-virals and immunopotentiators
US7576115B2 (en) 2003-06-06 2009-08-18 Nissan Chemical Industries, Ltd. Heterocyclic compounds and thrombopoietin receptor activators
US7351841B2 (en) 2003-06-06 2008-04-01 Nissan Chemical Industries, Ltd. Heterocyclic compounds and thrombopoietin receptor activators
US8318796B2 (en) 2003-06-06 2012-11-27 Nissan Chemical Industries, Ltd. Heterocyclic compounds and thrombopoietin receptor activators
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
US8552031B2 (en) 2004-12-08 2013-10-08 Nissan Chemical Industries, Ltd. 3-ethylidenehydrazino substituted heterocyclic compounds as thrombopoietin receptor activators
WO2006062249A1 (en) * 2004-12-08 2006-06-15 Nissan Chemical Industries, Ltd. Substituted heterocyclic compound and thrombopoietin receptor activator
WO2006062247A1 (en) * 2004-12-08 2006-06-15 Nissan Chemical Industries, Ltd. Substituted heterocyclic compound and thrombopoietin receptor activator
US8134013B2 (en) 2004-12-14 2012-03-13 Nissan Chemical Industries, Ltd. Amide compound and thrombopoietin receptor activator
US7968542B2 (en) 2005-07-15 2011-06-28 Nissan Chemical Industries, Ltd. Thiophene compounds and thrombopoietin receptor activators
US7960425B2 (en) 2005-07-20 2011-06-14 Nissan Chemical Industries, Ltd. Pyrazole compounds and thrombopoietin receptor activators
US8026368B2 (en) 2005-11-07 2011-09-27 Nissan Chemical Industries, Ltd. Hydrazide compounds and thrombopoietin receptor activators
US8093251B2 (en) 2006-06-07 2012-01-10 Nissan Chemical Industries, Ltd. Nitrogen-containing heterocyclic compounds and thrombopoietin receptor activators
WO2007142308A1 (en) 2006-06-07 2007-12-13 Nissan Chemical Industries, Ltd. Nitrogen-containing heterocyclic compound and thrombopoietin receptor activator
US9284275B2 (en) 2007-01-11 2016-03-15 Critical Outcome Technologies Inc. Inhibitor compounds and cancer treatment methods
US8052993B2 (en) 2007-05-03 2011-11-08 Glaxosmithkline Llc 3′-[(2Z)-[1-(3,4-dimethylphenyl)-1,5-dihydro-3-methyl-5-oxo-4H-pyrazol-4-ylidene]hydrazino]-2′-hydroxy[1,1′-biphenyl]-3-carboxylic acid bis-(monoethanolamine)
US8828430B2 (en) 2007-05-03 2014-09-09 Glaxosmithkline Llc 3′-[(2Z)-[1-(3,4-dimethylphenyl)-1,5-dihydro-3-methyl-5-oxo-4H-pyrazol-4-ylidene]hydrazino]-2′-hydroxy-[1,1′-biphenyl]-3-carboxylic acid bis-(monoethanolamine)
US8062665B2 (en) 2007-05-03 2011-11-22 Glaxosmithkline Llc 3′-[(2Z)-[1-(3,4-dimethylphenyl)-1 ,5-dihydro-3-methyl-5-oxo-4H-pyrazol-4-ylidene]hydrazino]-2′-hydroxy-[1,1′-biphenyl]-3-carboxylic acid bis-(monoethanolamine)
US8071129B2 (en) 2007-05-03 2011-12-06 Glaxosmithkline Llc 3′-[(2Z)-[1-(3,4-dimethylphenyl)-1,5-dihydro-3-methyl-5-oxo-4H-pyrazol-4-ylidene]hydrazino]-2′-hydroxy-[1,1′-biphenyl]-3-carboxylic acid bis-(monoethanolamine)
US8052995B2 (en) 2007-05-03 2011-11-08 Glaxosmithkline Llc 3'-[(2Z)-[1-(3,4-dimethylphenyl)-1,5-dihydro-3-methyl-5-oxo-4H-pyrazol-4-ylidene] hydrazino]-2'-hydroxy-[1,1'-biphenyl]-3-carboxylic acid bis-(monoethanolamine)
US8052994B2 (en) 2007-05-03 2011-11-08 Glaxosmithkline Llc 3′-[(2Z)-[1-(3,4-dimethylphenyl)-1,5-dihydro-3-methyl-5-oxo-4H-pyrazol-4-ylidene] hydrazino]-2′-hydroxy-[1,1′-biphenyl]-3-carboxylic acid bis-(monoethanolamine)
US8895556B2 (en) 2007-12-26 2014-11-25 Critical Outcome Technologies Inc. Compounds and method for treatment of cancer
WO2009092276A1 (en) 2008-01-10 2009-07-30 Shanghai Hengrui Pharmaceutical Co., Ltd. Bicyclo-substituted pyrazolon azo derivatives, preparation process and pharmaceutical use thereof
US8367710B2 (en) 2008-01-10 2013-02-05 Jiangsu Hengrui Medicine Co. Ltd. Bicyclo-substituted pyrazolon azo derivatives, preparation process and pharmaceutical use thereof
US8927281B2 (en) 2008-10-30 2015-01-06 Irm Llc Method for expanding hematopoietic stem cells
EP3524604A1 (en) 2008-10-30 2019-08-14 Novartis AG Expanded hematopoietic stem cells from cord blood and their therapeutic use
US9580426B2 (en) 2008-10-30 2017-02-28 Novartis Ag Compounds that expand hematopoietic stem cells
US8609693B2 (en) 2009-05-29 2013-12-17 Glaxosmithkline Llc Methods of administration of thrombopoietin agonist compounds
US9120762B2 (en) 2009-06-11 2015-09-01 Jiangsu Hengrui Medicine Co., Ltd. Salts of bicyclo-substituted pyrazolon azo derivatives, preparation method and use thereof
US8642637B2 (en) 2009-06-11 2014-02-04 Jiangsu Hengrui Medicine Co., Ltd. Salts of bicyclo-substituted pyrazolon azo derivatives, preparation method and use thereof
US9422282B2 (en) 2010-04-01 2016-08-23 Critical Outcome Technologies Inc. Compounds and method for treatment of HIV
US8987272B2 (en) 2010-04-01 2015-03-24 Critical Outcome Technologies Inc. Compounds and method for treatment of HIV
US9624220B2 (en) 2010-04-01 2017-04-18 Critical Outcome Technologies Inc. Compounds and method for treatment of HIV
WO2012102937A2 (en) 2011-01-25 2012-08-02 Irm Llc Compounds that expand hematopoietic stem cells
WO2013086436A1 (en) 2011-12-08 2013-06-13 Fred Hutchinson Cancer Research Center Compositions and methods for enhanced generation of hematopoietic stem/progenitor cells
US9834755B2 (en) 2011-12-08 2017-12-05 Fred Hutchinson Cancer Research Center Compositions and methods for enhanced generation of hematopoietic stem/progenitor cells
US9409906B2 (en) 2012-01-27 2016-08-09 Universite De Montreal Pyrimido[4,5-B]indole derivatives and use thereof in the expansion of hematopoietic stem cells
US10336747B2 (en) 2012-01-27 2019-07-02 Université de Montréal Pyrimido[4,5-B]indole derivatives and use thereof in the expansion of hematopoietic stem cells
WO2013110198A1 (en) 2012-01-27 2013-08-01 Université de Montréal Pyrimido[4,5-b]indole derivatives and use thereof in the expansion of hematopoietic stem cells
US10647718B2 (en) 2014-04-22 2020-05-12 Universitéde Montréal Compounds and use thereof in the expansion of hematopoietic stem cells and/or hematopoietic progenitor cells
US10724028B2 (en) 2014-10-31 2020-07-28 Nissan Chemical Industries, Ltd. Ligand-binding fiber and cell culture substrate using said fiber

Also Published As

Publication number Publication date
AU1462201A (en) 2001-06-06
JP2003513965A (en) 2003-04-15
EP1228051A1 (en) 2002-08-07

Similar Documents

Publication Publication Date Title
WO2001034585A1 (en) Semicarbazone derivatives and their use as thrombopoietin mimetics
US6552008B1 (en) Thrombopoietin mimetics
EP1213965B1 (en) Thrombopoietin mimetics
US6670387B1 (en) Thrombopoietin mimetics
EP1864981B1 (en) Thrombopoietin mimetics
US6498155B1 (en) Methods of treating thrombocytopenia
US7241783B2 (en) Thrombopoietin mimetics
EP1244446B1 (en) Thrombopoietin mimetics
WO2000066112A1 (en) Cxcr-4 receptor antagonists - thrombopoietin mimetics
WO2002085343A1 (en) Thrombopoietin mimetics
US6720345B1 (en) Semicarbazone derivatives and their use as thrombopoietin mimetics
US6858630B2 (en) Naphthimidazole derivatives and their use as thrombopoietin mimetics
US6875786B2 (en) Thrombopoietin mimetics
US6642265B1 (en) Thrombopoietin mimetics

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AU CA JP US

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE TR

121 Ep: the epo has been informed by wipo that ep was designated in this application
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
WWE Wipo information: entry into national phase

Ref document number: 10129211

Country of ref document: US

ENP Entry into the national phase

Ref country code: JP

Ref document number: 2001 536532

Kind code of ref document: A

Format of ref document f/p: F

WWE Wipo information: entry into national phase

Ref document number: 2000976915

Country of ref document: EP

WWP Wipo information: published in national office

Ref document number: 2000976915

Country of ref document: EP