51 results about "Thrombopoietin receptor" patented technology

Pharmaceutical compositions containing as an active ingredient compounds of the general formula (I), prodrugs of the same, pharmaceutically acceptable salts of both, or solvates of them and exhibiting thrombopoietin receptor agonism: X<1>-Y<1>-Z<1> (I) wherein X<1 >is optionally substituted aryl, optionally substituted heteroaryl or the like; Y<1 >is -NRCO-(CH2)0-2- or the like (wherein Ris hydrogen atom or the like); and Z<1 >is a cyclic group fused the same or different two ring selected from optionally substituted carbocyclic group and optionally substituted heterocyclic group.

This invention provides an agonist antibody to a human thrombopoietin receptor (alias: human c-Mpl). More particularly, this invention provides an agonist antibody to a human thrombopoietin receptor, wherein the agonist antibody comprises: antibody constant regions comprising (1) amino acid sequences in a heavy chain constant region and a light chain constant region of a human antibody, (2) an amino acid sequence of a heavy chain constant region with a domain substituted between human antibody subclasses, and an amino acid sequence of a light chain constant region of a human antibody, or (3) amino acid sequences comprising a deletion(s), substitution(s), addition(s), or insertion(s) of one or several amino acid residues in the amino acid sequences of (1) or (2) above; and antibody variable regions capable of binding to and activating a human thrombopoietin receptor; and wherein the agonist antibody has the properties: (a) that the antibody induces colony formation at a concentration of 10,000 ng / ml or lower as determined by the CFU-MK colony formation assay using human umbilical-cord-blood-derived CD34+ cells; and (b) that the antibody has a maximal activity at least 50% higher than that of PEG-rHuMGDF and an 50% effective concentration (EC50) of 100 nM or less in the cell proliferation assay using UT7 / TPO cell. Also provided is a pharmaceutical composition for treating thrombocytopenia comprising said antibody.

A compound represented by the formula (1): wherein A is a nitrogen atom or CR4, B is an oxygen atom, a sulfur atom or NR9 (provided that when A is a nitrogen atom, B is not NH), R1 is a C2-14 aryl group, L1 is a bond, CR10R11, an oxygen atom, a sulfur atom or NR12, X is OR13 SR13 or NR14NR15, R2 is a hydrogen atom, a formyl group, a C1-10 alkyl group or the like, L2 is a bond or the like, L3 is a bond, CR17R18, an oxygen atom, a sulfur atom or NR19, L4 is a bond, CR20R21, an oxygen atom, a sulfur atom or NR22, Y is an oxygen atom, a sulfur atom or NR23, and R3 is a C2-14 aryl group, a tautomer, prodrug or pharmaceutically acceptable salt of the compound or a solvate thereof.

The present inventors used antibody engineering techniques to prepare functional antibodies that correspond to individual mutations in causative genes of diseases, and discovered that such antibodies enable the treatment of the diseases. Specifically, the inventors succeeded in preparing ligands, particularly minibodies, which have agonistic activity to receptors that have almost completely lost responsiveness to their natural ligands because of gene mutations (for example, a thrombopoietin (TPO) receptor whose reactivity to TPO has been markedly impaired), and which can transduce signals by interacting with these mutant receptors at levels comparable to normal.

Peptides and compounds that bind to and activate the thrombopoietin receptor (c-mpl or TPO-R) or otherwise act as a TPO agonist are disclosed.

A preventive, therapeutic or improving agent for diseases against which activation of the thrombopoietin receptor is effective or a platelet increasing agent, which contains a thrombopoietin receptor activator represented by the formula (1): wherein A is a C?2-14#191 aryl group, B is a hydrogen atom, a C?1-6#191 alkyl group, a C?1-3#191 alkyl group substituted with one or more fluorine atoms or a C?2-14#191 aryl group, D is a hydrogen atom, a C?1-6#191 alkyl group, a C?1-3#191 alkyl group substituted with one or more fluorine atoms or a C?2-14#191 aryl group, and E is a C?2-14#191 aryl group, a tautomer, prodrug or pharmaceutically acceptable salt of the activator or a solvate thereof, as an active ingredient.

Peptide compounds that bind to and activate the thrombopoietin receptor (c-mpl or TPO-R) or otherwise act as a TPO agonist are disclosed.

Peptide compounds that bind to and activate the thrombopoietin receptor (c-mpl or TPO-R) or otherwise act as a TPO agonist are disclosed.

This invention provides an agonist antibody to a human thrombopoietin receptor (alias: human c-Mpl). More particularly, this invention provides an agonist antibody to a human thrombopoietin receptor, wherein the agonist antibody comprises: antibody constant regions comprising (1) amino acid sequences in a heavy chain constant region and a light chain constant region of a human antibody, (2) an amino acid sequence of a heavy chain constant region with a domain substituted between human antibody subclasses, and an amino acid sequence of a light chain constant region of a human antibody, or (3) amino acid sequences comprising a deletion(s), substitution(s), addition(s), or insertion(s) of one or several amino acid residues in the amino acid sequences of (1) or (2) above; and antibody variable regions capable of binding to and activating a human thrombopoietin receptor; and wherein the agonist antibody has the properties: (a) that the antibody induces colony formation at a concentration of 10,000 ng / ml or lower as determined by the CFU-MK colony formation assay using human umbilical-cord-blood-derived CD34+ cells; and (b) that the antibody has a maximal activity at least 50% higher than that of PEG-rHuMGDF and an 50% effective concentration (EC50) of 100 nM or less in the cell proliferation assay using UT7 / TPO cell. Also provided is a pharmaceutical composition for treating thrombocytopenia comprising said antibody.

A compound represented by the general formula (I): wherein R1 is a hydrogen atom, a halogen atom, or the like; R2, R3, and R4 are each independently a hydrogen atom, a halogen atom, C1-C15 alkyl optionally substituted with one or more C1-C12 alkyloxy or the like, or the like; R5 is a hydrogen atom or the like; R6 and R7 are a hydrogen atom or the like; R8 is C1-C3 alkyl or the like; R9 is a hydrogen atom or the like), a prodrug, a pharmaceutically acceptable salt, or solvate thereof.

The present invention relates to: a method for producing an intermediate having high chemical purity and / or high optical purity; a crystal of an intermediate having high chemical purity and / or optical purity; a method for producing an intermediate, in which two reactions can be carried out sequentially substantially in a single step; and a method for producing an optically active 1,3-thiazole derivative having an agonistic activity on thrombopoietin receptors.

The present invention provides compounds useful for prevention, treatment or alleviation of diseases against which activation of the thrombopoietin receptor is effective.A compound represented by the formula (1):wherein A, B, R1, L1, R2, L2, L3, Y, L4, R3 and X are the same as defined in the description, a tautomer, prodrug or pharmaceutically acceptable salt of the compound or a solvate thereof.

The present inventor has found out that the following criteria enable to ensure an effect for increasing the platelet count while preventing an excessive increase in the platelet count;“when the platelet count has increased by a certain amount and reached to a sufficient level of the platelet count during administration of a pharmaceutical composition containing a compound having a thrombopoietin receptor agonistic activity, administration of the pharmaceutical composition is discontinued thereafter”.

A preventive, therapeutic or improving agent for diseases against which activation of the thrombopoietin receptor is effective or a platelet increasing agent, which contains a thrombopoietin receptor activator represented by the formula (1): [wherein each of R1 and R3 is independently a hydrogen atom, SO3H, a C1-6 alkyl group, a C1-6 alkylcarbonyl group or a C6-18 arylcarbonyl group (the C1-6 alkyl group, the C1-6 alkylcarbonyl group and the C6-18 arylcarbonyl group may be optionally substituted with a halogen atom, a hydroxyl group, a C2-6 alkenyl group, a C1-6 alkoxy group, a C1-6 alkoxycarbonyl group, a C6-18 aryl group, a 2-pyridyl group, a 3-pyridyl group, a 4-pyridyl group, a 2-furanyl group, a 3-furanyl group, a 2-thienyl group, a 3-thienyl group or NR9R10) , and each of R2, R4 and Ra is independently a hydrogen atom, a hydroxyl group or a C1-6 alkoxy group].

A compound represented by the formula (I) (wherein R1, R2, R3 and R4 are as defined in the description), a tautomer, prodrug or pharmaceutically acceptable salt of the compound or a solvate thereof.

The present invention relates to a synthetic variable region of an immunoglobin construct which contains in at least one of its CDRs a sequence of thrombopoietin, e.g., IEGPTLRQWLAARA or its derivatives. This construct can efficiently bind and activate a thrombopoientin receptor (MPL) leading to stimulation of proliferation, growth or differentiation or modulation of apoptosis of hematopoietic cells, especially platelet progenitor cells. The invention further relates to the use of the synthebody to treat hematopoietic or immune disorders, and particularly thrombocytopenia resulting from chemotherapy, radiation therapy, or bone marrow transfusions.

The present invention discloses cell lines and recombinant growth factor receptors useful in adoptive cell therapy (ACT), wherein the recombinant growth factor receptor can act as a molecular switch enabling cells expressing the rGFR protein to be expanded in-vitro or in- vivo. Thus the invention provides a T or NK cell, comprising a recombinant growth factor receptor (rGFR) comprising: (i) an extracellular (EC) domain; (ii) a thrombopoietin receptor transmembrane (TM) domain; and (iii) a growth factor receptor intracellular (IC) domain.

The invention discloses a synthesizing method for 3'-amino-2'-hydroxy biphenyl-3-carboxylic acid.2-bromine-6-nitrophenol serves as a staring material, 2-bromine-6-aminophenol is obtained through a reduction reaction, ring formation and Suzuki coupling are carried out, a hydrolysis reaction is carried out, and 3'-amino-2'-hydroxy biphenyl-3-carboxylic acid is obtained. According to the method, raw materials are easy to obtain, the path is short, and the method is novel, low in cost, high in yield and environmentally friendly. Tests show that the obtained product is reliable in quality, stable in performance and capable of being further used for preparing a thrombopoietin receptor stimulant, namely, eltrombopag olamine.

The present invention discloses an agonistic antibody directed against human thrombopoietin receptor (also referred to as 'human c-Mpl). Specifically, the antibody has a constant region having a set of amino acid sequences selected from the following items (1) to (3): (1) amino acid sequences for a heavy-chain constant region and a light-chain constant region of a human antibody; (2) an amino acid sequence for a human antibody heavy-chain constant region in which the domain is replaced by one of other human antibody subclass and an amino acid sequence for a human antibody light-chain constant region; and (3) a set of amino acid sequences having the deletion, substitution, addition or insertion of one or several amino acid residues in each of the amino acid sequences shown in (1) and (2), and the antibody has a variable region capable of binding to a human thrombopoietin receptor to activate the receptor. The antibody also has the following properties: (a) the antibody can induce the formation of a colony at a concentration of 10,000 ng / mL or less in the CFU-MK colony formation assay using a human umbilical cord blood CD34+ cell; and (b) the antibody has the maximum activity higher than that of PEG-rHuMGDF by 50% or more and a 50% effective concentration (EC50) of 100 nM or less in the cell growth assay using an UT7 / TPO cell. Also disclosed is a pharmaceutical composition for the treatment of thrombocytopenia, which comprises the antibody.

A compound represented by the formula (I) (wherein R1, R2, R3 and R4 are as defined in the description), a tautomer, prodrug or pharmaceutically acceptable salt of the compound or a solvate thereof.

A method is disclosed for the treatment of human subjects diagnosed with immune thrombocytopenia (ITP). The method comprises administering to a human subject a human neonatal Fc receptor (hFcRn) antagonist, optionally in combination with standard-of-care ITP treatment. In certain embodiments, the hFcRn antagonist is efgartigimod (ARGX-113). Standard-of-care ITP treatment may comprise administration of corticosteroids, immunosuppressants, and / or thrombopoietin receptor (TPO-R) agonists.

A compound represented by the general formula (I):wherein R1 is a hydrogen atom, a halogen atom, or the like; R2, R3, and R4 are each independently a hydrogen atom, a halogen atom, C1-C15 alkyl optionally substituted with one or more C1-C12 alkyloxy or the like, or the like; R5 is a hydrogen atom or the like; R6 and R7 are a hydrogen atom or the like; R8 is C1-C3 alkyl or the like; R9 is a hydrogen atom or the like), a prodrug, a pharmaceutically acceptable salt, or solvate thereof.

The invention discloses an analysis method for evaluating in-vitro activity of a thrombopoietin (TPO) receptor stimulant. According to the method, the binding activity of a sample and a TPO receptor and the activity of the thrombopoietin are reflected by evaluating the proliferation-promoting development capacity of the sample on cells. By adopting the method, on one hand, the problem that BaF3-hMpl cell system in the prior art is great in establishing difficulty, great in time consumption and instable in detection result can be solved; on the other hand, the problems that by adopting a suspension cell MTT method, the color developing time is long, an insoluble formazan product is generated, the result reproductivity is poor and the accuracy is low can be solved; meanwhile, a four-parameter data processing method which is better than survival rate evaluation indexes is adopted, so that the activity value of the sample can be directly defined.