WO2002085343A1 - Mimetiques de la thrombopoietine - Google Patents

Mimetiques de la thrombopoietine Download PDF

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Publication number
WO2002085343A1
WO2002085343A1 PCT/US2002/006259 US0206259W WO02085343A1 WO 2002085343 A1 WO2002085343 A1 WO 2002085343A1 US 0206259 W US0206259 W US 0206259W WO 02085343 A1 WO02085343 A1 WO 02085343A1
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Prior art keywords
substituted
compound
alkyl
aryl
cycloalkyl
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PCT/US2002/006259
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English (en)
Inventor
Kevin J. Duffy
Juan I. Luengo
Antony N. Shaw
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Smithkline Beecham Corporation
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Priority to US10/469,365 priority Critical patent/US6875786B2/en
Priority to JP2002582917A priority patent/JP2004527541A/ja
Priority to EP02728383A priority patent/EP1370252A4/fr
Publication of WO2002085343A1 publication Critical patent/WO2002085343A1/fr

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    • 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):
  • R, R1 , R2 and R ⁇ are each independently selected from hydrogen, Cj.galkyl, -(CH2)pOR4, -C(0)OR , formyl, nitro, cyano, halogen, aryl, substituted aryl, substituted alkyl, -S(0) n R 4 , cycloalkyl, -NR 5 R 6 > protected -OH, -CONR 5 R 6 , phosphonic acid, sulfonic acid, phosphinic acid and -S ⁇ 2NR ⁇ R", where p is 0-6, n is 0-2,
  • 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 4 is hydrogen, alkyl, cycloalkyl, C ⁇ -C]2aryl, substituted alkyl, substituted cycloalkyl and substituted C j -C ⁇ aryl; and RIO and R ⁇ are independently hydrogen, cycloalkyl, Cj-C ] 2 ar yl > substituted cycloalkyl, substituted Ci -C ⁇ 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 4 , -S(0) n R 4 -C(0)NR 4 R 4 , - S(0)2NR 4 R 4 , nitro, cyano, cycloalkyl, substituted cycloalkyl, halogen, aryl, substituted aryl and protected -OH, or RlO and R* * taken together with the nitrogen to which they are attached represent
  • 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.
  • 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.
  • R, R1 , R ⁇ and R ⁇ are each independently selected from hydrogen, C j .galkyl,
  • -(CH2)pOR 4 -C(0)OR 4 , formyl, nitro, cyano, halogen, aryl, substituted aryl, substituted alkyl, -S(0) n R 4 cycloalkyl, -NR 5 R 6 , protected -OH, -CONR 5 R 6 , phosphonic acid, sulfonic acid, phosphinic acid and -S ⁇ 2NR ⁇ R", where p is 0-6, n is 0-2,
  • 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;
  • Y is selected from alkyl, substituted alkyl and a cyclic or polycyclic aromatic ring containing from 3 to 14 carbon atoms and optionally containing from one to three 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, Ci -C ⁇ aryl, substituted cycloalkyl, substituted C ⁇ -C]2aryl, hydroxy, aryloxy, alkoxy, cycloalkyl, nitro, cyano, halogen and protected -OH and pharmaceutically acceptable salts, hydrates, solvates and esters thereof;
  • R, Rl, R ⁇ and R ⁇ is a substituted aryl group.
  • R is a substituted aryl; and R* is hydrogen;
  • R is hydrogen; and R ⁇ is a substituted aryl
  • 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.
  • C ] -Ci 2aryl 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.
  • 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
  • alkoxy as used herein is meant -Oalkyl where alkyl is as described herein including -OCH 3 and -OC(CH ) 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, 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.
  • treating and derivatives thereof as used herein, is meant prophylatic and 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 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:
  • a compound of this invention was active in an in vitro proliferation assay using the human UT7TPO cell line.
  • UT7TPO cells are a human megakaryoblastic cell line that express Tpo-R, whose survival and growth 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.
  • 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.
  • Example 3 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'- ⁇ [l-(3,4-Dimethylphenyl)-3-methyl- 5-oxo-l,5-dihydropyrazol-4-ylidenemethyl]amino ⁇ -2'-hydroxybiphenyl-3-carboxylic acid in 10% by volume propylene glycol in water.
  • sucrose, calcium sulfate dihydrate and a presently invented agonist of the TPO receptor are mixed and granulated in the proportions shown with a 10% gelatin solution.
  • the wet granules are screened, dried, mixed with the starch, talc and stearic acid, screened and compressed into a tablet.

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Abstract

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.
PCT/US2002/006259 2001-03-01 2002-03-01 Mimetiques de la thrombopoietine WO2002085343A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
US10/469,365 US6875786B2 (en) 2001-03-01 2002-03-01 Thrombopoietin mimetics
JP2002582917A JP2004527541A (ja) 2001-03-01 2002-03-01 トロンボポエチン模倣物
EP02728383A EP1370252A4 (fr) 2001-03-01 2002-03-01 Mimetiques de la thrombopoietine

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US26995801P 2001-03-01 2001-03-01
US60/269,958 2001-03-01

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WO2004108683A1 (fr) * 2003-06-06 2004-12-16 Nissan Chemical Industries, Ltd. Utilisation de composes heteroaryles a substitution 3-alkylidenehydrazino en tant qu'activateurs du recepteur de la thrombopoietine
EP1622609A2 (fr) * 2003-04-29 2006-02-08 Smithkline Beecham Corporation Procedes de traitement de maladies/lesions degeneratives
WO2006062240A1 (fr) * 2004-12-08 2006-06-15 Nissan Chemical Industries, Ltd. Composes heterocycliques a substitution 3-ethylidenehydrazino utilises en tant qu’activateurs du recepteur de la thrombopoietine
US7160870B2 (en) 2000-05-25 2007-01-09 Smithkline Beecham Corporation Thrombopoietin mimetics
WO2007062078A2 (fr) * 2005-11-23 2007-05-31 Ligand Pharmaceuticals Inc. Composes modulant l'activite thrombopoietine et procedes correspondants
WO2007142308A1 (fr) 2006-06-07 2007-12-13 Nissan Chemical Industries, Ltd. Composé hétérocyclique azoté et activateur de récepteur de thrombopoïétine
CN100443472C (zh) * 2003-06-06 2008-12-17 日产化学工业株式会社 3-亚烷基肼基取代的杂芳基化合物以及含有其的药物
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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
WO2011098095A1 (fr) 2010-02-09 2011-08-18 Aplagen Gmbh Peptides se liant au récepteur de tpo
US8026368B2 (en) 2005-11-07 2011-09-27 Nissan Chemical Industries, Ltd. Hydrazide compounds and thrombopoietin receptor activators
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)
US8053453B2 (en) 2002-10-09 2011-11-08 Nissan Chemical Industries, Ltd. Pyrazolone compounds and thrombopoietin receptor activator
US8134013B2 (en) 2004-12-14 2012-03-13 Nissan Chemical Industries, Ltd. Amide compound and thrombopoietin receptor activator
WO2012102937A2 (fr) 2011-01-25 2012-08-02 Irm Llc Composés qui développent des cellules souches hématopoïétiques
WO2013086436A1 (fr) 2011-12-08 2013-06-13 Fred Hutchinson Cancer Research Center Compositions et procédés pour la génération améliorée de cellules souches/progénitrices hématopoïétiques
WO2013110198A1 (fr) 2012-01-27 2013-08-01 Université de Montréal Dérivés de pyrimido[4,5-b]indole et leur utilisation dans l'expansion des cellules souches hématopoïétiques
US8609693B2 (en) 2009-05-29 2013-12-17 Glaxosmithkline Llc Methods of administration of thrombopoietin agonist compounds
US8927281B2 (en) 2008-10-30 2015-01-06 Irm Llc Method for expanding hematopoietic stem cells
CN104628647A (zh) * 2013-11-12 2015-05-20 上海医药工业研究院 3-甲基-1-(3,4-二甲基苯基)-2-吡唑啉-5-酮的制备方法
RU2569885C2 (ru) * 2010-11-02 2015-12-10 Ниссан Кемикал Индастриз, Лтд. Органические аминные соли производных аминобензойной кислоты и способ их получения
CN110467531A (zh) * 2018-05-09 2019-11-19 新发药业有限公司 一种3’-硝基-2’-羟基联苯-3-甲酸的制备方法
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

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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
US7160870B2 (en) 2000-05-25 2007-01-09 Smithkline Beecham Corporation Thrombopoietin mimetics
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US7648971B2 (en) 2000-05-25 2010-01-19 Smithkline Beecham Corp. Thrombopoietin mimetics
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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)
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)
US7851503B2 (en) 2002-08-14 2010-12-14 Nissan Chemical Industries, Ltd. Thrombopoetin receptor activator and process for producing the same
US8053453B2 (en) 2002-10-09 2011-11-08 Nissan Chemical Industries, Ltd. Pyrazolone compounds and thrombopoietin receptor activator
EP1622609A2 (fr) * 2003-04-29 2006-02-08 Smithkline Beecham Corporation Procedes de traitement de maladies/lesions degeneratives
EP1622609A4 (fr) * 2003-04-29 2008-09-03 Smithkline Beecham Corp Procedes de traitement de maladies/lesions degeneratives
US7576115B2 (en) 2003-06-06 2009-08-18 Nissan Chemical Industries, Ltd. Heterocyclic compounds and thrombopoietin receptor activators
JP2010006821A (ja) * 2003-06-06 2010-01-14 Nissan Chem Ind Ltd ヒドラジド化合物の製造方法
US8318796B2 (en) 2003-06-06 2012-11-27 Nissan Chemical Industries, Ltd. Heterocyclic compounds and thrombopoietin receptor activators
CN100443472C (zh) * 2003-06-06 2008-12-17 日产化学工业株式会社 3-亚烷基肼基取代的杂芳基化合物以及含有其的药物
KR101211975B1 (ko) 2003-06-06 2012-12-13 닛산 가가쿠 고교 가부시키 가이샤 트롬보포이에틴 수용체 활성화제로서의3-알킬리덴히드라지노 치환 헤테로아릴 화합물
US7351841B2 (en) 2003-06-06 2008-04-01 Nissan Chemical Industries, Ltd. Heterocyclic compounds and thrombopoietin receptor activators
WO2004108683A1 (fr) * 2003-06-06 2004-12-16 Nissan Chemical Industries, Ltd. Utilisation de composes heteroaryles a substitution 3-alkylidenehydrazino en tant qu'activateurs du recepteur de la thrombopoietine
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
WO2006062240A1 (fr) * 2004-12-08 2006-06-15 Nissan Chemical Industries, Ltd. Composes heterocycliques a substitution 3-ethylidenehydrazino utilises en tant qu’activateurs du recepteur de la thrombopoietine
US8552031B2 (en) 2004-12-08 2013-10-08 Nissan Chemical Industries, Ltd. 3-ethylidenehydrazino substituted heterocyclic compounds as thrombopoietin receptor activators
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
WO2007062078A3 (fr) * 2005-11-23 2007-12-21 Ligand Pharm Inc Composes modulant l'activite thrombopoietine et procedes correspondants
WO2007062078A2 (fr) * 2005-11-23 2007-05-31 Ligand Pharmaceuticals Inc. Composes modulant l'activite thrombopoietine et procedes correspondants
US8093251B2 (en) 2006-06-07 2012-01-10 Nissan Chemical Industries, Ltd. Nitrogen-containing heterocyclic compounds and thrombopoietin receptor activators
WO2007142308A1 (fr) 2006-06-07 2007-12-13 Nissan Chemical Industries, Ltd. Composé hétérocyclique azoté et activateur de récepteur de thrombopoïétine
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)
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)
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)
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)
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EP3524604A1 (fr) 2008-10-30 2019-08-14 Novartis AG Cellules souches hématopoïétiques propagées obtenues à partir de sang du cordon ombilical, et leur utilisation thérapeutique
US9580426B2 (en) 2008-10-30 2017-02-28 Novartis Ag Compounds that expand hematopoietic stem cells
US8927281B2 (en) 2008-10-30 2015-01-06 Irm Llc Method for expanding hematopoietic stem cells
US8609693B2 (en) 2009-05-29 2013-12-17 Glaxosmithkline Llc Methods of administration of thrombopoietin agonist compounds
WO2011098095A1 (fr) 2010-02-09 2011-08-18 Aplagen Gmbh Peptides se liant au récepteur de tpo
RU2569885C2 (ru) * 2010-11-02 2015-12-10 Ниссан Кемикал Индастриз, Лтд. Органические аминные соли производных аминобензойной кислоты и способ их получения
WO2012102937A2 (fr) 2011-01-25 2012-08-02 Irm Llc Composés qui développent des cellules souches hématopoïétiques
US9834755B2 (en) 2011-12-08 2017-12-05 Fred Hutchinson Cancer Research Center Compositions and methods for enhanced generation of hematopoietic stem/progenitor cells
WO2013086436A1 (fr) 2011-12-08 2013-06-13 Fred Hutchinson Cancer Research Center Compositions et procédés pour la génération améliorée de cellules souches/progénitrices hématopoïétiques
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
WO2013110198A1 (fr) 2012-01-27 2013-08-01 Université de Montréal Dérivés de pyrimido[4,5-b]indole et leur utilisation dans l'expansion des cellules souches hématopoïétiques
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
CN104628647A (zh) * 2013-11-12 2015-05-20 上海医药工业研究院 3-甲基-1-(3,4-二甲基苯基)-2-吡唑啉-5-酮的制备方法
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
CN110467531A (zh) * 2018-05-09 2019-11-19 新发药业有限公司 一种3’-硝基-2’-羟基联苯-3-甲酸的制备方法
CN110467531B (zh) * 2018-05-09 2022-04-19 新发药业有限公司 一种3’-硝基-2’-羟基联苯-3-甲酸的制备方法

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