WO2016056652A1 - Inhibiteur de la fibrose de la moelle osseuse - Google Patents

Inhibiteur de la fibrose de la moelle osseuse Download PDF

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Publication number
WO2016056652A1
WO2016056652A1 PCT/JP2015/078775 JP2015078775W WO2016056652A1 WO 2016056652 A1 WO2016056652 A1 WO 2016056652A1 JP 2015078775 W JP2015078775 W JP 2015078775W WO 2016056652 A1 WO2016056652 A1 WO 2016056652A1
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Prior art keywords
compound
solvate
myelofibrosis
acceptable salt
pharmaceutically acceptable
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PCT/JP2015/078775
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English (en)
Japanese (ja)
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和哉 下田
光太郎 幣
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国立大学法人 宮崎大学
日本新薬株式会社
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Publication of WO2016056652A1 publication Critical patent/WO2016056652A1/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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/166—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca

Definitions

  • the present invention relates to N-[(2R) -2,3-dihydroxypropoxy] -3,4-difluoro-2-[(2-fluoro-4-iodophenyl) amino] benzamide (hereinafter referred to as “Compound A”). Or a pharmaceutically acceptable salt thereof or a solvate thereof, and a pharmaceutical composition for inhibiting bone marrow fibrosis associated with myelofibrosis.
  • the present invention also relates to myelofibrosis comprising Compound A or a pharmaceutically acceptable salt or solvate thereof, and a compound having a JAK2 inhibitory action or a pharmaceutically acceptable salt or solvate thereof.
  • the present invention relates to a pharmaceutical composition for suppressing accompanying fibrosis of bone marrow.
  • Compound A is known to exhibit antitumor activity against various solid cancers (see, for example, Patent Document 1 and Non-Patent Document 1). There is no report that it is effective for fibrosis.
  • Myelofibrosis is a general term for diseases that cause widespread fibrosis in the bone marrow, and is broadly divided into primary myelofibrosis and secondary myelofibrosis that occurs with other diseases.
  • primary myelofibrosis hematopoietic stem cells have undergone neoplastic growth, and cytokines are secreted from abnormal clones centered on megakaryocytes, and fibroblasts proliferate reactively, resulting in bone marrow fibrosis. proceed.
  • primary myelofibrosis in addition to bone marrow fibrosis, various clinical symptoms such as hematopoietic failure, splenomegaly, and worsening of systemic symptoms are exhibited.
  • Secondary myelofibrosis is secondary to various diseases, but is often secondary to myelodysplastic syndrome, polycythemia vera, and essential thrombocythemia.
  • a gene mutation in which the 617th amino acid of Janus kinase 2 (hereinafter referred to as “JAK2”) was substituted from valine to phenylalanine was found.
  • JAK2 activation is considered to be one of the causes of the development of primary myelofibrosis, and clinical trials of JAK2 inhibitors have been promoted for primary myelofibrosis.
  • JAK2 inhibitors that have been used clinically so far have a certain effect on splenomegaly reduction but are not very effective against bone marrow fibrosis (for example, non-patented References 2 and 3), there has been a strong demand for a new drug capable of suppressing bone marrow fibrosis.
  • An object of the present invention is to provide a novel pharmaceutical composition that can suppress, for example, bone marrow fibrosis associated with myelofibrosis.
  • the present inventors have used Compound A or a pharmaceutically acceptable salt thereof or a solvate thereof. Or a compound A or a pharmaceutically acceptable salt thereof or a solvate thereof, and a compound having a JAK2 inhibitory action or a pharmaceutically acceptable salt thereof or a solvate thereof, in combination to prevent myelofibrosis. It was found that the accompanying fibrosis of the bone marrow can be suppressed, and the present invention has been completed.
  • examples of the present invention include the following.
  • a pharmaceutical composition for inhibiting bone marrow fibrosis associated with myelofibrosis comprising Compound A or a pharmaceutically acceptable salt thereof or a solvate thereof.
  • Bone marrow associated with myelofibrosis containing Compound A or a pharmaceutically acceptable salt or solvate thereof, and a compound having a JAK2 inhibitory action or a pharmaceutically acceptable salt or solvate thereof A pharmaceutical composition for inhibiting fibrosis.
  • a combined pharmaceutical for suppressing bone marrow fibrosis associated with myelofibrosis comprising a combination of substances.
  • compound 10 As a compound having JAK2 inhibitory action, for example, (S) -N 2- [1- (4-fluorophenyl) ethyl] -4- (1-methyl-1H-pyrazol-4-yl) -N 6- (pyrazine -2-yl) pyridine-2,6-diamine (hereinafter also referred to as “compound 10”).
  • FIG. 1 shows a cross-sectional photograph of bone marrow in a myelofibrosis mouse after administration of 0.5% methylcellulose.
  • FIG. 2 shows a photograph of a bone marrow in a myelofibrotic mouse after administration of maleate of compound 10.
  • FIG. 3 shows a photograph of a bone marrow section in a myelofibrosis mouse after administration of Compound A.
  • FIG. 4 shows a photograph of a bone marrow section in a myelofibrosis mouse after administration of a combination of maleate of compound 10 and compound A.
  • FIG. 1 shows a cross-sectional photograph of bone marrow in a myelofibrosis mouse after administration of 0.5% methylcellulose.
  • FIG. 2 shows a photograph of a bone marrow in a myelofibrotic mouse after administration of maleate of compound 10.
  • FIG. 3 shows a photograph of a bone marrow section in a myelofibrosis mouse after administration of Compound
  • FIG. 5 shows wild-type mice (WT), myelofibrosis mice (TG), myelofibrosis mice after administration of maleate of compound 10 (maleate of compound 10), maleate of compound 10 and The spleen weight (g) in a myelofibrosis model mouse (Compound 10 maleate + Compound A) after administration in combination with Compound A and a myelofibrosis mouse (Compound A) after administration of Compound A is shown. .
  • FIG. 6 shows a photograph of a slice of the spleen in a myelofibrotic mouse after administration of 0.5% methylcellulose.
  • FIG. 7 shows a photograph of a slice of the spleen in a myelofibrotic mouse after administration of maleate of compound 10.
  • FIG. 8 shows a photograph of a slice of the spleen in a myelofibrotic mouse after administration of Compound A.
  • FIG. 9 shows a photograph of a slice of the spleen in a myelofibrotic mouse after administration of the maleate of compound 10 and compound A in combination.
  • FIG. 10 shows a photograph of a section of spleen tissue in myelofibrosis mice after administration of 0.5% methylcellulose.
  • FIG. 11 shows a photograph of a slice of spleen tissue in a myelofibrotic mouse after administration of maleate of compound 10.
  • FIG. 12 shows a photograph of a section of spleen tissue in a myelofibrosis mouse after administration of Compound A.
  • FIG. 13 shows a photograph of a section of spleen tissue in myelofibrosis mice after administration of a combination of maleate of compound 10 and compound A.
  • Examples of the present invention include a pharmaceutical composition for suppressing bone marrow fibrosis associated with myelofibrosis, which comprises Compound A or a pharmaceutically acceptable salt thereof or a solvate thereof.
  • a pharmaceutical composition containing compound A or a pharmaceutically acceptable salt thereof or a solvate thereof for inhibiting bone marrow fibrosis associated with myelofibrosis refers to one pharmaceutical composition to be administered.
  • an active ingredient for example, it means a pharmaceutical composition containing an amount of Compound A or a pharmaceutically acceptable salt or solvate thereof effective to suppress bone marrow fibrosis associated with myelofibrosis .
  • an effective amount of “an amount of Compound A or a pharmaceutically acceptable salt or solvate thereof effective to suppress bone marrow fibrosis associated with myelofibrosis” is included when entering a patient's body.
  • the amount necessary to suppress bone marrow fibrosis associated with myelofibrosis for example, taking into account the patient's condition such as age, weight, type of disease, degree, etc., and the route of administration
  • it is usually 0.01 mg per day in the case of oral administration as an active ingredient amount of Compound A or a pharmaceutically acceptable salt or solvate thereof for an adult (body weight of about 60 kg).
  • the range of ⁇ 5 g / adult, preferably 1 mg ⁇ 500 mg / adult is appropriate. In some cases, less than this may be sufficient, and vice versa.
  • composition containing Compound A or a pharmaceutically acceptable salt thereof or a solvate thereof may be administered daily or intermittently, and may be administered once or two to three times per day. Can be divided into two.
  • myelofibrosis examples include primary myelofibrosis and secondary myelofibrosis caused by other diseases.
  • primary myelofibrosis examples include myelofibrosis caused by JAK2V617F mutation, myelofibrosis caused by JAK2 activated by strong expression of thrombopoietin, or activating mutation of thrombopoietin receptor (MPL).
  • MPL thrombopoietin receptor
  • W515L mutation myelofibrosis caused by (W515L mutation).
  • secondary myelofibrosis examples include myelofibrosis secondary to myelodysplastic syndrome, myelofibrosis secondary to true polycythemia, or myelofibrosis secondary to essential thrombocythemia. it can.
  • a pharmaceutical composition containing Compound A or a pharmaceutically acceptable salt thereof or a solvate thereof can be expected, for example, to suppress bone marrow fibrosis associated with myelofibrosis. Can be used for
  • a pharmaceutical composition containing Compound A or a pharmaceutically acceptable salt thereof or a solvate thereof is a compound having JAK2 inhibitory activity or a pharmaceutical thereof known to be usable as a therapeutic agent for myelofibrosis. You may use together with the pharmaceutical composition containing the top acceptable salt or its solvate.
  • Examples of the “compound having a JAK2 inhibitory action” include the following compounds.
  • Compound 1 3 (R) -cyclopentyl-3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl] propanenitrile (eg, patent (Refer to Literature 2 and Patent Literature 3).
  • Compound 2 N-tert-butyl-3- (5-methyl-2- ⁇ 4- [2- (1-pyrrolidinyl) ethoxy] phenylamino ⁇ pyrimidin-4-ylamino) benzenesulfonamide (eg, patent (Ref.
  • compound having JAK2 inhibitory action is, for example, compound 10 ((S) —N 2- [1- (4-fluorophenyl) ethyl] -4- (1-methyl-1H-pyrazol-4-yl) ) -N 6- (pyrazin-2-yl) pyridine-2,6-diamine).
  • the “pharmaceutically acceptable salt” is not particularly limited as long as it is pharmaceutically acceptable.
  • a salt with an inorganic base a salt with an organic base, a salt with an inorganic acid, a salt with an organic acid
  • examples of the salt with an inorganic base include alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as calcium salt and magnesium salt, aluminum salt and ammonium salt.
  • salts with organic bases include salts with trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, and N, N′-dibenzylethylenediamine.
  • Examples of the salt with an inorganic acid include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, and phosphoric acid.
  • salts with organic acids include formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p Mention may be made of salts with toluenesulfonic acid.
  • the pharmaceutically acceptable salt of the compound having JAK2 inhibitory action specifically, the phosphate of compound 1, the hydrochloride of compound 4, the dihydrochloride of compound 6, the maleate of compound 10, and the compound 11 Mention may be made of citrate, citrate of compound 12, and hydrobromide of compound 16.
  • “Solvates” of “compounds having JAK2 inhibitory action or pharmaceutically acceptable salts or solvates thereof” include solvates of compounds having JAK2 inhibitory action and pharmaceuticals of compounds having JAK2 inhibitory action Mention may be made of solvates of the above acceptable salts.
  • “Solvate” of “Compound A or a pharmaceutically acceptable salt or solvate thereof” includes a solvate of Compound A or a solvate of a pharmaceutically acceptable salt of Compound A.
  • Examples of solvates include solvates with water (hydrates) and solvates with organic solvents such as alcohols and sulfoxides. Specifically, dimethyl sulfoxide solvates of compound A Can be mentioned.
  • Bone marrow associated with myelofibrosis comprising Compound A or a pharmaceutically acceptable salt or solvate thereof, and a compound having a JAK2 inhibitory activity or a pharmaceutically acceptable salt or solvate thereof, as the present invention
  • the pharmaceutical composition for suppressing the fibrosis of can be mentioned.
  • the present invention also includes a pharmaceutical composition containing Compound A or a pharmaceutically acceptable salt thereof or a solvate thereof, and a compound having a JAK2 inhibitory action or a pharmaceutically acceptable salt thereof or a solvate thereof.
  • a combination medicine for suppressing bone marrow fibrosis associated with myelofibrosis which is a combination of the pharmaceutical compositions.
  • a pharmaceutical composition for inhibiting refers to (a) an amount of compound A effective to inhibit bone marrow fibrosis associated with myelofibrosis or its compound as an active ingredient in one administered drug A pharmaceutically acceptable salt or solvate thereof, and (b) an effective amount of a compound having JAK2 inhibitory action or a pharmaceutically acceptable salt or solvate thereof for treating myelofibrosis
  • the pharmaceutical composition for suppressing the fibrosis of the bone marrow accompanying myelofibrosis is meant.
  • an effective amount of a “compound having a JAK2 inhibitory effect or a pharmaceutically acceptable salt or solvate thereof effective for treating myelofibrosis” when entering a patient's body is, for example, It is the amount necessary to reduce splenomegaly, which is one of the main symptoms of myelofibrosis. For example, it should be prepared in consideration of the patient's condition such as age, weight, type of disease, degree of administration, etc. However, in general, the amount of the active ingredient of a compound having a JAK2 inhibitory action or a pharmaceutically acceptable salt or solvate thereof for an adult (body weight of about 60 kg) is orally administered per day. , 0.01 mg to 5 g / adult, preferably 1 mg to 500 mg / adult. In some cases, less than this may be sufficient, and vice versa.
  • a pharmaceutical composition containing, for example, a compound A or a pharmaceutically acceptable salt or solvate thereof, and a compound having a JAK2 inhibitory action or a pharmaceutically acceptable salt or solvate thereof as an active ingredient may be administered daily or intermittently, and the number of administrations per day can be once or divided into 2 to 3 times.
  • a pharmaceutical composition containing Compound A or a pharmaceutically acceptable salt thereof or a solvate thereof, and a compound having a JAK2 inhibitory action or a pharmaceutically acceptable salt thereof or a solvate thereof is, for example, for myelofibrosis It can be used to treat myelofibrosis because it can be expected to suppress the accompanying fibrosis of the bone marrow and reduce splenomegaly.
  • “Combination medicine for inhibiting bone marrow fibrosis associated with myelofibrosis” in combination is, for example, (a) an effective amount of an effective ingredient for inhibiting bone marrow fibrosis associated with myelofibrosis A pharmaceutical composition comprising Compound A or a pharmaceutically acceptable salt thereof or a solvate thereof; and (b) a compound having a JAK2 inhibitory effect effective for treating myelofibrosis as an active ingredient or a pharmaceutical thereof It means a medicament for suppressing bone marrow fibrosis associated with myelofibrosis, which is a group of pharmaceutical compositions containing the above acceptable salts or solvates thereof.
  • a pharmaceutical composition containing Compound A or a pharmaceutically acceptable salt or solvate thereof and a pharmaceutical composition containing a compound having a JAK2 inhibitory action or a pharmaceutically acceptable salt or solvate thereof can be mentioned, for example.
  • a specific kit form for example, a blister package (for example, PTP sheet) in which both pharmaceutical compositions corresponding to a specific period are packaged together in one sheet according to a series of administration schedules in the manufacturing stage of the pharmaceutical composition.
  • both pharmaceutical compositions can be mentioned in the same package for each use.
  • a pharmaceutical composition containing Compound A or a pharmaceutically acceptable salt thereof or a solvate thereof and a pharmaceutical composition containing a compound having a JAK2 inhibitory action or a pharmaceutically acceptable salt thereof or a solvate thereof When formulated as a pharmaceutical composition, or a pharmaceutical composition containing Compound A or a pharmaceutically acceptable salt or solvate thereof, and a compound having a JAK2 inhibitory activity or a pharmaceutically acceptable salt or solvate thereof When a pharmaceutical comprising a combination of pharmaceutical compositions containing products is formulated, the respective pharmaceutical compositions can be administered simultaneously or sequentially. When each pharmaceutical composition is administered sequentially, for example, each pharmaceutical composition can be used in different administration schedules. Moreover, the case where each pharmaceutical composition is administered with a fixed time interval, and the case where one pharmaceutical composition is administered for a certain period of time and then the other pharmaceutical composition are included are also included.
  • each pharmaceutical composition may be in the same dosage form or in different dosage forms.
  • each administration route may be the same or different.
  • a pharmaceutical composition containing, for example, a compound A or a pharmaceutically acceptable salt thereof or a solvate thereof and a compound having a JAK2 inhibitory action or a pharmaceutically acceptable salt or solvate thereof as an active ingredient for example, a compounding agent
  • a pharmaceutically acceptable non-toxic and inert carrier for example, 0.001% to 99.5%, preferably 0.1% to 90% As that medicament is administered to mammals including humans.
  • the carrier one or more solid, semi-solid, or liquid diluents, fillers, and other prescription auxiliary agents are used.
  • the pharmaceutical composition according to the present invention is a solid or liquid dosage unit, and is a powder, powder, capsule, tablet, syrup, suspension, liquid, dragee, granule, elixir, troche and the like.
  • Any form of parenteral preparations such as administration preparations, injections, ointments, lotions and creams can be used. It may be a sustained-release preparation. Among them, the preparation for oral administration is preferable.
  • the pharmaceutical composition according to the present invention can be formulated by using a known formulation technique, and for example, can be performed by using the following method.
  • compound A or a pharmaceutically acceptable salt or solvate thereof and / or a compound having a JAK2 inhibitory action or a pharmaceutically acceptable salt or solvate thereof should be appropriately finely divided.
  • the powder is compound A or a pharmaceutically acceptable salt or solvate thereof, and / or a compound having a JAK2 inhibitory action or a pharmaceutically acceptable salt or solvate thereof, and is finely divided. It can be produced by mixing with a finely divided pharmaceutical carrier, for example, an edible carbohydrate such as starch or mannitol.
  • flavor, etc. can be added arbitrarily.
  • Capsules are produced by first filling a powdered powder, powder, or a granulated product as described in the section above into a capsule shell such as a gelatin capsule as described above. be able to.
  • Lubricants and fluidizing agents such as colloidal silica, talc, magnesium stearate, calcium stearate, solid polyethylene glycol are mixed with powdered powders and powders and then filled. It can also be manufactured.
  • disintegrating agents and solubilizers such as carboxymethyl cellulose, carboxymethyl cellulose calcium, low-substituted hydroxypropyl cellulose, croscarmellose sodium, carboxymethyl starch sodium, calcium carbonate, sodium carbonate can be added.
  • compound A or a pharmaceutically acceptable salt thereof or a solvate thereof, and / or a fine powder of a compound having a JAK2 inhibitory action or a pharmaceutically acceptable salt thereof or a solvate thereof is added to vegetable oil, polyethylene glycol, glycerin. Alternatively, it can be suspended and dispersed in a surfactant and wrapped in a gelatin sheet to form a soft capsule.
  • the tablet is prepared by adding an excipient to powdered compound A or a pharmaceutically acceptable salt or solvate thereof, and / or a compound having a JAK2 inhibitory action or a pharmaceutically acceptable salt or solvate thereof.
  • it can be produced by making a powder mixture, granulating or slugging, then adding a disintegrant or lubricant and then tableting.
  • a syrup is prepared by dissolving Compound A or a pharmaceutically acceptable salt thereof or a solvate thereof and / or a compound having a JAK2 inhibitory action or a pharmaceutically acceptable salt thereof or a solvate thereof in an appropriate flavor aqueous solution.
  • An elixir can be produced by using a non-toxic alcoholic carrier.
  • the suspension is prepared by dispersing Compound A or a pharmaceutically acceptable salt or solvate thereof and / or a compound having a JAK2 inhibitory action or a pharmaceutically acceptable salt or solvate thereof in a non-toxic carrier.
  • a non-toxic carrier can be manufactured.
  • solubilizers and emulsifiers for example, ethoxylated isostearic alcohols, polyoxyethylene sorbitol esters
  • preservatives for example, ethoxylated isostearic alcohols, polyoxyethylene sorbitol esters
  • flavoring agents for example, peppermint oil, saccharin
  • dosage unit formulations for oral administration can be microencapsulated.
  • the formulation can also be extended in action time or sustained release by being coated or embedded in a polymer, wax or the like.
  • the injection is prepared by subjecting a certain amount of Compound A or a pharmaceutically acceptable salt or solvate thereof and / or a compound having a JAK2 inhibitory action or a pharmaceutically acceptable salt or solvate thereof to the purpose of injection.
  • Non-toxic salts and salt solutions can be added to make the injection isotonic.
  • stabilizers, preservatives, emulsifiers, and the like can be added.
  • the ointment is, for example, compound A or a pharmaceutically acceptable salt or solvate thereof, and / or a compound having a JAK2 inhibitory action or a pharmaceutically acceptable salt or solvate thereof and a hydrophobic base, It can manufacture by mixing bases, such as a hydrophilic base. Further, a preservative, an antioxidant and the like can be added.
  • the lotion includes, for example, Compound A or a pharmaceutically acceptable salt thereof or a solvate thereof, and / or a compound having a JAK2 inhibitory action or a pharmaceutically acceptable salt thereof or a solvate thereof, a solvent, an emulsifier, a suspension.
  • Liquid agents, troches, and elixirs may also be used in certain amounts of Compound A or a pharmaceutically acceptable salt or solvate thereof, and / or a compound having a JAK2 inhibitory activity or a pharmaceutically acceptable salt or solvate thereof. Dosage unit form may contain a certain amount of product.
  • the present invention will be described in more detail with reference to test examples, but the present invention is not limited thereto.
  • a JAK2V617F transgenic mouse exhibiting bone marrow and spleen fibrosis, spleen enlargement, etc. was used (see, for example, Non-Patent Document 7).
  • (A) 0.5% methylcellulose solution (Wako Pure Chemical Industries, Ltd. CAT. No.
  • Test Example 1 Examination of bone marrow fibrosis inhibitory activity using myelofibrosis mice Myelofibrosis mice to which no drug was administered, myelofibrosis mice to which compound 10 maleate was administered, myelofibrosis mice to which compound A was administered
  • the femur and tibia obtained from myelofibrosis mice administered with maleate of compound 10 and compound A were formalin-fixed and then embedded in paraffin (5-6 mice in each group). The paraffin section was used for staining with silver and the fiber component was stained.
  • a photograph of a representative femur is shown in FIGS.
  • the myelofibrosis mouse administered with Compound A or the maleate of Compound 10 which is a JAK2 inhibitor and Compound A and the myelofibrosis mouse administered with Compound A are compared with those in the non-drug-administered myelofibrosis mouse. It is clear that bone marrow fibrosis is suppressed.
  • Test Example 2 Examination of spleen weight using myelofibrosis mice Wild-type mice without administration of drugs, myelofibrosis mice without administration of drugs, myelofibrosis mice with administration of maleate of compound 10, administration of compound A
  • the spleens collected from the myelofibrosis mice and the myelofibrosis mice administered with maleate of Compound 10 and Compound A were measured (10 to 16 mice in each group). The result is shown in FIG. From these results, it is clear that the myeloid fibrosis mice administered with maleic acid 10 and compound A, which have a JAK2 inhibitory action, have a lighter spleen weight than the non-drug-administered myelofibrosis mice.
  • Test Example 3 Examination of Splenic Fibrosis Inhibiting Action Using Myelofibrosis Mice Myelofibrosis Mice Not Administered with Drug, Myelofibrosis Mice Administered Maleate of Compound 10, Myelofibrosis Administered Compound A Spleens collected from mice and myelofibrosis mice administered with maleate of compound 10 and compound A were fixed in formalin and embedded in paraffin (5-6 mice in each group). The paraffin section was used for staining with silver and the fiber component was stained. Representative photographs are shown in FIGS. 7 to 10 as an example.
  • the myelofibrosis mouse administered with Compound A or the maleate of Compound 10 which is a JAK2 inhibitor and Compound A and the myelofibrosis mouse administered with Compound A are compared with those in the non-drug-administered myelofibrosis mouse. It is clear that spleen fibrosis is suppressed.
  • Test Example 4 Examination of spleen function using myelofibrosis mice Myelofibrosis mice to which no drug was administered, myelofibrosis mice to which maleate of compound 10 was administered, myelofibrosis mice to which compound A was administered, and compounds Spleens collected from myelofibrosis mice administered with 10 maleates and Compound A were fixed in formalin and embedded in paraffin (5-6 mice in each group). Hematoxylin and eosin staining was performed using paraffin sections. Representative photographs are shown in FIGS. 11 to 14 as an example.

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Abstract

L'invention concerne une nouvelle composition pharmacologique permettant de supprimer la fibrose de la moelle osseuse associée à la myélofibrose. Des exemples de l'invention concernent : (1) un produit pharmaceutique destiné à supprimer la fibrose de la moelle osseuse associée à la myélofibrose, ledit produit contenant N-[(2R)-2,3-dihydroxypropoxy]-3,4-difluoro-2-[(2-fluoro-4-iodophényl)amino]benzamide ou un sel ou solvate pharmacologiquement acceptable de celui-ci ; (2) une composition pharmacologique destinée à supprimer la fibrose de la moelle osseuse associée à la myélofibrose, ladite composition contenant N-[(2R)-2,3-dihydroxypropoxy]-3,4-difluoro-2-[(2-fluoro-4-iodophényl)amino]benzamide ou un sel ou solvate pharmacologiquement acceptable de celui-ci, ainsi qu'un composé doté d'un effet inhibiteur de JAK2 ou un sel ou solvate pharmacologiquement acceptable de celui-ci ; et analogue.
PCT/JP2015/078775 2014-10-09 2015-10-09 Inhibiteur de la fibrose de la moelle osseuse WO2016056652A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006061712A2 (fr) * 2004-12-10 2006-06-15 Pfizer Inc. Utilisation d'inhibiteurs de mek dans le traitement d'une croissance cellulaire anormale
WO2010090290A1 (fr) * 2009-02-06 2010-08-12 日本新薬株式会社 Dérivé d'aminopyrazine et médicament correspondant

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006061712A2 (fr) * 2004-12-10 2006-06-15 Pfizer Inc. Utilisation d'inhibiteurs de mek dans le traitement d'une croissance cellulaire anormale
WO2010090290A1 (fr) * 2009-02-06 2010-08-12 日本新薬株式会社 Dérivé d'aminopyrazine et médicament correspondant

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