EP1370252A1 - Mimetiques de la thrombopoietine - Google Patents

Mimetiques de la thrombopoietine

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Publication number
EP1370252A1
EP1370252A1 EP02728383A EP02728383A EP1370252A1 EP 1370252 A1 EP1370252 A1 EP 1370252A1 EP 02728383 A EP02728383 A EP 02728383A EP 02728383 A EP02728383 A EP 02728383A EP 1370252 A1 EP1370252 A1 EP 1370252A1
Authority
EP
European Patent Office
Prior art keywords
substituted
compound
alkyl
aryl
cycloalkyl
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP02728383A
Other languages
German (de)
English (en)
Other versions
EP1370252A4 (fr
Inventor
Kevin J. Duffy
Juan I. Luengo
Antony N. Shaw
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
GlaxoSmithKline LLC
Original Assignee
SmithKline Beecham Corp
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Filing date
Publication date
Application filed by SmithKline Beecham Corp filed Critical SmithKline Beecham Corp
Publication of EP1370252A1 publication Critical patent/EP1370252A1/fr
Publication of EP1370252A4 publication Critical patent/EP1370252A4/fr
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/04—Nitro compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D231/18—One oxygen or sulfur atom
    • C07D231/20—One oxygen atom attached in position 3 or 5

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 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 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.
  • 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. Hematologv/Oncology 14: 8-21 (1992).
  • Thrombopoietin is a glycoprotein with at least two forms, with apparent molecular masses of 25 kDa and 31 kDa, with a common N-terminal amino acid sequence. See, Bartley, et al., Cell 77: 1117-1124 (1994). Thrombopoietin appears to have 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-a and interferon-b. 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.
  • This invention relates to compounds of Formula (I):
  • R4 is hydrogen, alkyl, cycloalkyl, C ] -C ] 2aryl, substituted alkyl, substituted cycloalkyl and substituted C ⁇ -C ] 2aryl, and
  • R-> and R" are each independently selected from hydrogen, alkyl, substituted alkyl, C3_6cycloalkyl, and aryl, or R-> and R" taken together with the nitrogen to which they are attached represent a 5 to 6 member saturated ring containing up to one other heteroatom selected from oxygen and nitrogen;
  • R ⁇ is selected from hydrogen, C j -Ci Q alkyl and substituted C ] -C j ⁇ alkyl;
  • n 0-6;
  • AR is a cyclic or polycyclic aromatic ring containing from 3 to 16 carbon atoms and optionally containing one or more 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, and optionally substituted with one or more substituents selected from the group consisting of: alkyl, substituted alkyl, aryl, substituted cycloalkyl, substituted aryl, aryloxy, oxo, hydroxy, alkoxy, cycloalkyl, acyloxy, amino, N-acylamino, nitro, cyano, halogen, -C(0)OR 4 , -C(O)NR 10 R 1 J , -
  • R, R', R ⁇ and R ⁇ is a substituted aryl group.
  • 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.
  • novel processes and novel intermediates useful in preparing the presently invented TPO mimetic compounds include pharmaceutical compositions comprising a pharmaceutical carrier and compounds useful in the methods of the invention.
  • This invention relates to compounds of Formula (I) as described above.
  • R, R1 , R ⁇ and R ⁇ are each independently selected from hydrogen, C j .galkyl,
  • R 4 is hydrogen, alkyl, cycloalkyl, C j -C ⁇ aryl, substituted alkyl, substituted cycloalkyl and substituted C ⁇ -Cj2aryl, and
  • R ⁇ and R" are each independently selected from hydrogen, alkyl, substituted alkyl, C3_ ⁇ 5cycloalkyl, and aryl, or R ⁇ and R" taken together with the nitrogen to which they are attached represent a 5 to 6 member saturated ring containing up to one other heteroatom selected from oxygen and nitrogen;
  • R15 is selected from the group consisting of alkyl, C 1-C12aryl, hydroxy, substituted alkyl, substituted Ci-C ⁇ aryl and halogen;
  • n 0-6;
  • R, Rl, R ⁇ and R ⁇ is a substituted aryl group.
  • R is a substituted aryl; and R* is hydrogen;
  • R2 and R ⁇ are each independently selected from hydrogen, Cj.galkyl, Cj. ⁇ alkoxy, nitro, cyano, halogen, aryl, substituted aryl, substituted alkyl, cycloalkyl, phosphonic acid, phosphinic acid and sulfonic acid;
  • R ' 5 is selected from the group consisting of alkyl, substituted alkyl, C j -C ⁇ aryl, alkoxy and halogen; m is 0-4; and
  • Y is selected from, phenyl, pyridinyl and pyrimidinyl, where the phenyl, pyridinyl and pyrimidinyl are optionally substituted with from one to three substituents selected from the group consisting of: alkyl, substituted alkyl, C j -C ⁇ aryl, substituted Cj-C ⁇ aryl, alkoxy and halogen;
  • R is a substituted
  • R1 is hydrogen
  • R2 and R ⁇ are each independently selected from hydrogen, C j . ⁇ alkyl, C ⁇ alkoxy, nitro, cyano, halogen, substituted alkyl and cycloalkyl;
  • R* is selected from the group consisting of alkyl, substituted alkyl, Ci-C ⁇ aryl, alkoxy and halogen;
  • n 0-2;
  • Y is selected from, phenyl, pyridinyl and pyrimidinyl, where the phenyl, pyridinyl and pyrimidinyl are optionally substituted with from one to three substituents selected from the group consisting of: alkyl, substituted alkyl, C]-C]2 ryl, substituted C
  • R' is hydrogen
  • R ⁇ and R are each independently selected from hydrogen, Ci .galkyl, substituted alkyl and halogen;
  • R! 5 is selected from the group consisting of C j _4alkyl, C j ⁇ alkoxy, Cj-Cj ⁇ aryl and halogen;
  • n 0;
  • Y is selected from, phenyl, pyridinyl and pyrimidinyl, where the or phenyl, pyridinyl and pyrimidinyl is optionally substituted with from one to three substituents selected from the group consisting of: alkyl, substituted alkyl, Cj-C ⁇ aryl, substituted Cj-C ] 2aryl, alkoxy and halogen;
  • 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 -OH” as used herein, is meant the alcoholic or carboxylic-OH groups which can be protected by conventional blocking groups in the art such 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.
  • 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: -C0 2 R 2 °, aryl, -C(0)NHS(0) R 20 , -NHS(0) 2 R 2 °, hydroxyalkyl, alkoxy, - C(0)NR 21 R 22 , acyloxy, alkyl, amino, N-acylamino, hydroxy, -(CH 2 ) g C(0)OR 8 , -S(0) n R°, nitro, tetrazole, cyano, oxo, halogen, trifluoromethyl and protected -OH, where g is 0-6, R° is hydrogen or alkyl, RTM is selected form hydrogen, C j -C4alkyl, aryl and trifluoromethyl, and R 2 * and R 22 are independently selected form hydrogen, C ⁇ -C4alkyl, aryl and trifluoromethyl, and
  • 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, cyclopropyl and cyclopentyl.
  • acyloxy as used herein is meant -OC(0)alkyl where alkyl is as described herein.
  • 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 -Oaryl where aryl 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)gC(0)OR°, -S(0) n R° ⁇ nitro, cyano, halogen and protected -OH, where g is 0-6, R° is hydrogen or alkyl, and n is 0-2.
  • 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, and unless otherwise defined, the carbon chain will contain from 1 to 12 carbon atoms.
  • 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 Formulas I and II are prepared as shown in Schemes I to IV below, or by analogous methods, wherein the TL' substituents, AR, Y and m are as defined in Formulas I and II respectively and provided that the 'R' and m substituents, AR and Y do not include any such substituents that render inoperative the processes of
  • nitric acid sulfuric acid
  • ii) 4-carboxyphenylboronic acid Pd(PPh 3 ) 4 , Na2C03, dioxane, water
  • ARCOR NaOAc, water, EtOH.
  • Scheme I outlines the formation of Formula I compounds.
  • a 3-bromophenol (a) is nitrated with nitric acid or sodium nitrate and sulfuric acid to give nitro phenol (b).
  • a substituted arylboronic acid such as 3- carboxyphenylboronic acid or 4-carboxyphenylboronic acid in the presence of a catalyst, preferably tetrakistriphenylphosphino palladium and a base such as sodium carbonate ot triethylamine in a suitable solvent such as aqueous 1,4-dioxane or dimethylformamide afforded substituted aryl compound (c).
  • Scheme II outlines an alternative synthesis of Formula I compounds.
  • a 2- bromophenol (0 such as 2-bromoanisole or 2-bromo-5-methylanisole is nitrated with nitric acid or sodium nitrate and sulfuric acid to give nitro compound (g).
  • Removal of the protecting group is accomplished using an protic or Lewis acid such as concentrated hydrobromic acid, boron tribromide or trimethylsilyl iodide to affored the phenol (j)- Reduction of the nitro group by catalytic hydrogenation or mediated by a reducing metal such as iron of tin dichloride in a suitable solvent such as ethanol, acetic acid or water gives the aniline (k) Compound (k) is reacted with an aldehyde or ketone in aqueous ethanol preferably in the presence of sodium acetate to give the final product (1).
  • an protic or Lewis acid such as concentrated hydrobromic acid, boron tribromide or trimethylsilyl iodide to affored the phenol (j)- Reduction of the nitro group by catalytic hydrogenation or mediated by a reducing metal such as iron of tin dichloride in a suitable solvent such as ethanol, acetic acid or water gives the aniline (k) Compound
  • Scheme III outline a further procedure for the synthesis of Formula I compounds.
  • a catalyst preferably tetrakistriphenylphosphino palla
  • Removal of the protecting group Prot is accomplished using an protic or Lewis acid such as concentrated hydrobromic acid, boron tribromide or trimethylsilyl iodide to affored the phenol (o).
  • an protic or Lewis acid such as concentrated hydrobromic acid, boron tribromide or trimethylsilyl iodide to affored the phenol (o).
  • Nitration of (o) with nitric acid or sodium nitrate in the presence of an acid such as acetic or hydrochloric acid affords the nitro compound (p).
  • Scheme IV outlines the formation of pyrazoles for use in scheme I- III.
  • An amine such as 4-methylaniline, compound (s)
  • an appropriate acid such as hydrochloric acid, nitric acid or sulfuric acid in an appropriate aqueous solvent system such as water or ethanol-water mixtures then reduced in situ by tin chloride to afford hydrazine, compound (t).
  • the hydrazine is then condensed with a electrophilic carbonyl species such as ethyl acetoacetate (u), ethyl cyanoacetate or diethyl malonate, in an appropriate solvent such as acetic acid or ethanol at an appropriate temperature typically 0-100°C to give the corresponding pyrazole, compound (v).
  • a electrophilic carbonyl species such as ethyl acetoacetate (u), ethyl cyanoacetate or diethyl malonate
  • an appropriate solvent such as acetic acid or ethanol
  • Heating (v) with the reagent generated from phosphorus oxychloride and dimethylformamide, typically at 100 °C gives the pyrazole aldehyde (w) as described herein.
  • the treatment of thrombocytopenia, as described herein, 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 following assays are employed:
  • the compound of Example 1 promoted the proliferation of 32D-mpl cells at a concentration of 0.03 to 30 uM. (EC 50 /uM, %TPO max 0.67, 85%)
  • the present invention therefore provides a method of treating thrombocytopenia and other conditions with depressed platelet production, which comprises administering a compound of Formula (I) or a pharmaceutically acceptable salt, hydrate, solvate or ester 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.
  • 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.
  • Contemplated Equivalents It will be appreciated by the person of ordinary skill in the art that the compounds of Formulas I and II may also exist in tautomeric forms. For example, in Formula I, the double bond that is drawn between the nitrogen atom and the carbon atom exists between the carbon atom and the AR substituent. Tautomeric forms of the compounds of Formulas I and II are exemplified by the following Formula (III):
  • Phosphorus oxychloride (4.82 mL, 51.6 mmol) was added dropwise to an ice-cooled, stirred suspension of l-(3,4-dimethylphenyl)-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.
  • 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.
  • 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

La présente invention concerne des mimétiques TPO non peptidiques, une méthode de traitement de la thrombocytopénie, chez un mammifère, y compris chez l'homme, nécessitant un tel traitement. Cette méthode de traitement consiste à administrer à ce mammifère, une quantité efficace d'un dérivé hydroxy-1-azobenzène sélectionné.
EP02728383A 2001-03-01 2002-03-01 Mimetiques de la thrombopoietine Withdrawn EP1370252A4 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US26995801P 2001-03-01 2001-03-01
US269958P 2001-03-01
PCT/US2002/006259 WO2002085343A1 (fr) 2001-03-01 2002-03-01 Mimetiques de la thrombopoietine

Publications (2)

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EP1370252A1 true EP1370252A1 (fr) 2003-12-17
EP1370252A4 EP1370252A4 (fr) 2006-04-05

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