WO2016056652A1 - Inhibitor of bone marrow fibrosis - Google Patents

Inhibitor of bone marrow fibrosis 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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French (fr)
Japanese (ja)
Inventor
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/en

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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.

Abstract

The purpose of the present invention is to provide a novel pharmacological composition with which it is possible to suppress the fibrosis of bone marrow associated with myelofibrosis. Examples of the present invention include: (1) a pharmaceutical for suppressing the fibrosis of bone marrow associated with myelofibrosis, the pharmaceutical containing N-[(2R)-2,3-dihydroxypropoxy]-3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]benzamide or a pharmacologically acceptable salt or solvate thereof; (2) a pharmacological composition for suppressing the fibrosis of bone marrow associated with myelofibrosis, the pharmacological composition including N-[(2R)-2,3-dihydroxypropoxy]-3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]benzamide or a pharmacologically acceptable salt or solvate thereof, and a compound having a JAK2-inhibiting effect or a pharmacologically acceptable salt or solvate thereof; and the like.

Description

骨髄線維化の抑制剤Bone marrow fibrosis inhibitor
　本発明は、Ｎ－［（２Ｒ）－２，３－ジヒドロキシプロポキシ］－３，４－ジフルオロ－２－［（２－フルオロ－４－ヨードフェニル）アミノ］ベンズアミド（以下、「化合物Ａ」という。）若しくはその医薬上許容される塩又はその溶媒和物を含有する、骨髄線維症に伴う骨髄の線維化を抑制するための医薬組成物に関するものである。
　また、本発明は、化合物Ａ若しくはその医薬上許容される塩又はその溶媒和物、及びＪＡＫ２阻害作用を有する化合物若しくはその医薬上許容される塩又はその溶媒和物を含有する、骨髄線維症に伴う骨髄の線維化を抑制するための医薬組成物に関するものである。
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.
　化合物Ａは、各種固形癌に対して抗腫瘍作用を示すことが知られているが（例えば、特許文献１、非特許文献１を参照）、これまでに化合物Ａが骨髄線維症に伴う骨髄の線維化に有効であるとの報告はない。
　骨髄線維症は骨髄に広範な線維化をきたす疾患の総称であり、原発性骨髄線維症と他疾患に伴って生じる続発性骨髄線維症に大別される。
　原発性骨髄線維症では、造血幹細胞が腫瘍性増殖をきたし、そこで生じた巨核球を中心とした異常クローンからサイトカインが分泌されて線維芽細胞が反応性に増殖することで、骨髄の線維化が進行する。原発性骨髄線維症では、骨髄の線維化のほか、造血不全、脾腫大、全身症状の悪化など様々な臨床症状を示す。二次性骨髄線維症は種々の疾患に続発するが、骨髄異形成症候群、真正多血症、本態性血小板血症に続発することが多い。
　原発性骨髄線維症の約半数の症例において、Ｊａｎｕｓ　ｋｉｎａｓｅ　２（以下、「ＪＡＫ２」という。）の６１７番目のアミノ酸がバリンからフェニルアラニンへ置換された遺伝子変異（ＪＡＫ２Ｖ６１７Ｆ変異）が見出されたことから、ＪＡＫ２の活性化が原発性骨髄線維症発症の原因の一つと考えられ、原発性骨髄線維症に対してＪＡＫ２阻害剤の臨床試験が進められてきた。
　しかしながら、これまでに臨床使用されたＪＡＫ２阻害剤は脾腫の縮小に対して一定の効果はあるが、骨髄の線維化に対してはあまり有効ではないとの報告があるため、（例えば、非特許文献２、３を参照）、骨髄の線維化を抑制しうる新たな薬剤の提供が切望されていた。
　また、これまでにＪＡＫ２阻害剤とセリン／スレオニンキナーゼ阻害剤との併用療法に関する報告はあるが、細胞増殖抑制作用についての考察はあるものの、骨髄の線維化について考察されている報告はない（非特許文献４，５，６を参照）。
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.
In 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. In 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.
In about half of the cases of primary myelofibrosis, a gene mutation (JAK2V617F 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.
However, 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.
In addition, there have been reports on combination therapy with JAK2 inhibitors and serine / threonine kinase inhibitors so far, but there is no report on bone marrow fibrosis, although there are considerations on cell growth inhibitory action (non-) (See Patent Documents 4, 5, and 6).
ＷＯ２００２／００６２１３WO2002 / 006213 ＷＯ２００７／０７０５１４WO2007 / 070514 ＷＯ２００８／１５７２０８WO2008 / 157208 ＷＯ２００７／０５３４５２WO2007 / 053452 ＷＯ２００７／０５８６２７WO2007 / 058627 ＷＯ２００６／０７０１９５WO2006 / 070195 ＷＯ２０１０／０７４９４７WO2010 / 074947 ＷＯ２００８／１０９９４３WO2008 / 109943 ＷＯ２００７／０４９０４１WO2007 / 049041 ＷＯ２００７／０８９７６８WO2007 / 0897768 ＷＯ２０１１／０２８８６４WO2011 / 028864 ＷＯ２０１０／０９０２９０WO2010 / 090290 ＷＯ２００１／０４２２４６WO2001 / 042246 ＷＯ２００２／０９６９０９WO2002 / 096909 ＷＯ２００３／０４８１６２WO2003 / 048162 ＷＯ２００７／０５８６２８WO2007 / 058628 ＷＯ２０１１／０９７５２５WO2011-097525 ＷＯ２００９／１１４５１２WO2009 / 114512 ＷＯ２００７／０５８６２７WO2007 / 058627 ＷＯ２００５／０３７８００WO2005 / 037800 ＷＯ２０１０／０４６０３５WO2010 / 046035 ＷＯ２０１２／０３０８８５WO2012 / 03085 ＷＯ２０１０／１４９７６９WO2010 / 149769 ＷＯ２００７／０８４５５７WO2007 / 084557
　本発明の目的は、例えば、骨髄線維症に伴う骨髄の線維化を抑制しうる新規な医薬組成物を提供することにある。
An object of the present invention is to provide a novel pharmaceutical composition that can suppress, for example, bone marrow fibrosis associated with myelofibrosis.
　本発明者らは、骨髄線維症に伴う骨髄の線維化を抑制し得る新規な医薬を見出すべく、鋭意検討した結果、化合物Ａ若しくはその医薬上許容される塩又はその溶媒和物を用いることにより、または、化合物Ａ若しくはその医薬上許容される塩又はその溶媒和物、及びＪＡＫ２阻害作用を有する化合物若しくはその医薬上許容される塩又はその溶媒和物を組み合わせて用いることにより、骨髄線維症に伴う骨髄の線維化を抑制しうることを見出し、本発明の完成に至った。
As a result of intensive investigations to find a novel drug capable of suppressing 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.
　即ち、本発明として、例えば、以下のものを挙げることができる。
（１）化合物Ａ若しくはその医薬上許容される塩又はその溶媒和物を含有する、骨髄線維症に伴う骨髄の線維化を抑制するための医薬組成物。
（２）化合物Ａ若しくはその医薬上許容される塩又はその溶媒和物、及びＪＡＫ２阻害作用を有する化合物若しくはその医薬上許容される塩又はその溶媒和物を含有する、骨髄線維症に伴う骨髄の線維化を抑制するための医薬組成物。
（３）化合物Ａ若しくはその医薬上許容される塩又はその溶媒和物を含有する医薬組成物、及びＪＡＫ２阻害作用を有する化合物若しくはその医薬上許容される塩又はその溶媒和物を含有する医薬組成物を組み合わせてなる、骨髄線維症に伴う骨髄の線維化を抑制するための組み合わせ医薬。
That is, examples of the present invention include the following.
(1) A pharmaceutical composition for inhibiting bone marrow fibrosis associated with myelofibrosis, comprising Compound A or a pharmaceutically acceptable salt thereof or a solvate thereof.
(2) 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.
(3) 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. A combined pharmaceutical for suppressing bone marrow fibrosis associated with myelofibrosis, comprising a combination of substances.
　ＪＡＫ２阻害作用を有する化合物として、例えば、（Ｓ）－Ｎ2－［１－（４－フルオロフェニル）エチル］－４－（１－メチル－１Ｈ－ピラゾール－４－イル）－Ｎ6－（ピラジン－２－イル）ピリジン－２，６－ジアミン（以下、「化合物１０」ともいう。）を挙げることができる。
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”).
図１は、０．５％メチルセルロースを投与した後の骨髄線維症マウスにおける骨髄の切片写真を示す。FIG. 1 shows a cross-sectional photograph of bone marrow in a myelofibrosis mouse after administration of 0.5% methylcellulose. 図２は、化合物１０のマレイン酸塩を投与した後の骨髄線維症マウスにおける骨髄の切片写真を示す。FIG. 2 shows a photograph of a bone marrow in a myelofibrotic mouse after administration of maleate of compound 10. 図３は、化合物Ａを投与した後の骨髄線維症マウスにおける骨髄の切片写真を示す。FIG. 3 shows a photograph of a bone marrow section in a myelofibrosis mouse after administration of Compound A. 図４は、化合物１０のマレイン酸塩と化合物Ａを組み合わせて投与した後の骨髄線維症マウスにおける骨髄の切片写真を示す。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. 図５は、野生型マウス（ＷＴ）、骨髄線維症マウス（ＴＧ）、化合物１０のマレイン酸塩を投与した後の骨髄線維症マウス（化合物１０のマレイン酸塩）、化合物１０のマレイン酸塩と化合物Ａを組み合わせて投与した後の骨髄線維症モデルマウス（化合物１０のマレイン酸塩＋化合物Ａ）、及び化合物Ａを投与した後の骨髄線維症マウス（化合物Ａ）における脾臓重量（ｇ）を示す。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. . 図６は、０．５％メチルセルロースを投与した後の骨髄線維症マウスにおける脾臓の切片写真を示す。FIG. 6 shows a photograph of a slice of the spleen in a myelofibrotic mouse after administration of 0.5% methylcellulose. 図７は、化合物１０のマレイン酸塩を投与した後の骨髄線維症マウスにおける脾臓の切片写真を示す。FIG. 7 shows a photograph of a slice of the spleen in a myelofibrotic mouse after administration of maleate of compound 10. 図８は、化合物Ａを投与した後の骨髄線維症マウスにおける脾臓の切片写真を示す。FIG. 8 shows a photograph of a slice of the spleen in a myelofibrotic mouse after administration of Compound A. 図９は、化合物１０のマレイン酸塩と化合物Ａを組み合わせて投与した後の骨髄線維症マウスにおける脾臓の切片写真を示す。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. 図１０は、０．５％メチルセルロースを投与した後の骨髄線維症マウスにおける脾臓組織の切片写真を示す。FIG. 10 shows a photograph of a section of spleen tissue in myelofibrosis mice after administration of 0.5% methylcellulose. 図１１は、化合物１０のマレイン酸塩を投与した後の骨髄線維症マウスにおける脾臓組織の切片写真を示す。FIG. 11 shows a photograph of a slice of spleen tissue in a myelofibrotic mouse after administration of maleate of compound 10. 図１２は、化合物Ａを投与した後の骨髄線維症マウスにおける脾臓組織の切片写真を示す。FIG. 12 shows a photograph of a section of spleen tissue in a myelofibrosis mouse after administration of Compound A. 図１３は、化合物１０のマレイン酸塩と化合物Ａを組み合わせて投与した後の骨髄線維症マウスにおける脾臓組織の切片写真を示す。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.
　以下に本発明について詳述する。
The present invention is described in detail below.
　本発明として、化合物Ａ若しくはその医薬上許容される塩又はその溶媒和物を含有する、骨髄線維症に伴う骨髄の線維化を抑制するための医薬組成物を挙げることができる。 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.
　「化合物Ａ若しくはその医薬上許容される塩又はその溶媒和物を含有する、骨髄線維症に伴う骨髄の線維化を抑制するための医薬組成物」とは、投与される一つの医薬組成物中に、有効成分として、例えば、骨髄線維症に伴う骨髄の線維化を抑制するために有効な量の化合物Ａ若しくはその医薬上許容される塩又はその溶媒和物を含有する医薬組成物を意味する。 “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. In addition, as 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 .
　「骨髄線維症に伴う骨髄の線維化を抑制するために有効な量の化合物Ａ若しくはその医薬上許容される塩又はその溶媒和物」の有効な量としては、患者の体内に入ったときに、例えば、骨髄線維症に伴う骨髄の線維化を抑制するために必要な量であり、例えば、年齢、体重、疾病の種類、程度等の患者の状態、投与経路を考慮した上で調製することが望ましいが、通常は、成人（体重約６０ｋｇ）に対して、化合物Ａ若しくはその医薬上許容される塩又はその溶媒和物の有効成分量として、経口投与の場合、１日あたり、０．０１ｍｇ～５ｇ／成人の範囲内、好ましくは、１ｍｇ～５００ｍｇ／成人の範囲内が適当である。場合によっては、これ以下でも足りるし、また逆にこれ以上の用量を必要とすることもある。 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. For example, 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 However, 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.
　化合物Ａ若しくはその医薬上許容される塩又はその溶媒和物を含有する医薬組成物は、連日投与、又は間歇的に投与しても良く、一日当たりの投与回数は、１回または２～３回に分けて行うことができる。
The pharmaceutical 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.
　「骨髄線維症」としては、例えば、原発性骨髄線維症、他疾患に伴って生じる続発性骨髄線維症を挙げることができる。
　「原発性骨髄線維症」としては、例えば、ＪＡＫ２Ｖ６１７Ｆ変異が原因である骨髄線維症、トロンボポエチンの強発現により活性化されたＪＡＫ２が原因である骨髄線維症、又はトロンボポエチン受容体の活性化変異（ＭＰＬ　Ｗ５１５Ｌ変異）が原因である骨髄線維症を挙げることができる。
　「続発性骨髄線維症」としては、例えば、骨髄異形成症候群に続発する骨髄線維症、真正多血症に続発する骨髄線維症、又は本態性血小板血症に続発する骨髄線維症を挙げることができる。
Examples of “myelofibrosis” include primary myelofibrosis and secondary myelofibrosis caused by other diseases.
Examples of “primary myelofibrosis” include myelofibrosis caused by JAK2V617F mutation, myelofibrosis caused by JAK2 activated by strong expression of thrombopoietin, or activating mutation of thrombopoietin receptor (MPL). And myelofibrosis caused by (W515L mutation).
Examples of “secondary myelofibrosis” include myelofibrosis secondary to myelodysplastic syndrome, myelofibrosis secondary to true polycythemia, or myelofibrosis secondary to essential thrombocythemia. it can.
　化合物Ａ若しくはその医薬上許容される塩又はその溶媒和物を含有する医薬組成物は、例えば、骨髄線維症に伴う骨髄の線維化を抑制する効果が期待できることから、骨髄線維症を治療するために使用し得る。
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
　また、化合物Ａ若しくはその医薬上許容される塩又はその溶媒和物を含有する医薬組成物は、骨髄線維症の治療剤として使用しうることが知られているＪＡＫ２阻害作用を有する化合物若しくはその医薬上許容される塩又はその溶媒和物を含有する医薬組成物と併用してもよい。 In addition, 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.
　「ＪＡＫ２阻害作用を有する化合物」としては、例えば、以下の化合物を挙げることができる。
（１）化合物１：　３（Ｒ）－シクロペンチル－３－［４－（７Ｈ－ピロロ［２，３－ｄ］ピリミジン－４－イル）－１Ｈ－ピラゾール－１－イル］プロパンニトリル　（例えば、特許文献２，特許文献３を参照。）、
（２）化合物２：　Ｎ－ｔｅｒｔ－ブチル－３－（５－メチル－２－｛４－［２－（１－ピロリジニル）エトキシ］フェニルアミノ｝ピリミジン－４－イルアミノ）ベンゼンスルホンアミド　（例えば、特許文献４を参照。）、
（３）化合物３：　１１－［２－（１－ピロリジニル）エトキシ］－１４，１９－ジオキサ－５，７，２７－トリアザテトラシクロ［１９．３．１．１（２，６）．１（８，１２）］ヘプタコサ－１（２５），２（２７），３，５，８（２６），９，１１，１６，２１，２３－デカエン　（例えば、特許文献５を参照。）、
（４）化合物４：　Ｎ－シクロプロピル－Ｎ’－｛３－［５－（モルホリン－４－イルメチル）－１Ｈ－ベンズイミダゾール－２－イル］－１Ｈ－ピラゾール－４－イル｝ウレア　（例えば、特許文献６を参照。）、
（５）化合物５：　３－（４－クロロ－２－フルオロベンジル）－２－メチル－Ｎ－（５－メチル－１Ｈ－ピラゾール－３－イル）－８－（モルホリン－４－イルメチル）イミダゾ［１，２－ｂ］ピリダジン－６－アミン　（例えば、特許文献７を参照。）、
（６）化合物６：　Ｎ－（シアノメチル）－４－｛２－［４－（４－モルホリニル）フェニルアミノ］ピリミジン－４－イル｝ベンズアミド　（例えば、特許文献８を参照。）、
（７）化合物７：　（Ｓ）－５－クロロ－Ｎ２－［１－（５－フルオロピリミジン－２－イル）エチル］－Ｎ４－（５－メチル－１Ｈ－ピラゾール－３－イル）ピリミジン－２，４－ジアミン　（例えば、特許文献９を参照。）、
（８）化合物８：　Ｎ－［４－（２－｛［４－（モルホリン－４－イル）フェニル］アミノ｝ピリミジン－４－イル）フェニル］－Ｄ－プロリンアミド　（例えば、特許文献１０を参照。）、
（９）化合物９：　Ｎ，Ｎ－ジシクロプロピル－４－（１，５－ジメチル－１Ｈ－ピラゾール－３－イルアミノ）－６－エチル－１－メチル－１，６－ジヒドロイミダゾ［４，５－ｄ］ピロロ［２，３－ｂ］ピリジン－７－カルボキサミド　（例えば、特許文献１１を参照。）、
（１０）化合物１０：　（Ｓ）－Ｎ2－［１－（４－フルオロフェニル）エチル］－４－（１－メチル－１Ｈ－ピラゾール－４－イル）－Ｎ6－（ピラジン－２－イル）ピリジン－２，６－ジアミン　（例えば、特許文献１２を参照。）、
（１１）化合物１１：　３－｛４（Ｒ）－メチル－３（Ｒ）－［Ｎ－メチル－Ｎ－（７Ｈ－ピロロ［２，３－ｄ］ピリミジン－４－イル）アミノ］ピペリジン－１－イル｝－３－オキソプロパンニトリル　（例えば、特許文献１３，特許文献１４，特許文献１５を参照。）、
（１２）化合物１２：　１４－メチル－２０－オキサ－５，７，１４，２７－テトラアザテトラシクロ［１９．３．１．１（２，６）．１（８，１２）］ヘプタコサ－１（２５），２（２７），３，５，８（２６），９，１１，１６，２１，２３－デカエン　（例えば、特許文献１６，特許文献１７を参照。）、
（１３）化合物１３：　２－｛１－（エチルスルホニル）－３－［４－（７Ｈ－ピロロ［２，３－ｄ］ピリミジン－４－イル）－１Ｈ－ピラゾール－１－イル］アゼチジン－３－イル｝アセトニトリル　（例えば、特許文献１８を参照。）、
（１４）化合物１４：　９（Ｅ）－１５－［２－（１－ピロリジニル）エトキシ］－７，１２，２５－トリオキサ－１９，２１，２４－トリアザテトラシクロ［１８．３．１．１（２，５）．１（１４，１８）］ヘキサコサ－１（２４），２，４，９，１４（２６），１５，１７，２０，２２－ノナエン　（例えば、特許文献１９を参照。）、
（１５）化合物１５：　（２Ｒ，３Ｒ）－３－［（２－｛［４－（Ｓ－シクロプロピルスルホンイミドイル）フェニル］アミノ｝－５－（トリフルオロメチル）ピリミジン－４－イル）オキシ］ブタン－２－オール　（例えば、特許文献２０，特許文献２１を参照。）、
（１６）化合物１６：　（±）－（４－フルオロフェニル）｛４－［（５－メチル－１Ｈ－ピラゾール－３－イル）アミノ］キナゾリン－２－イル｝メタノール　（例えば、特許文献２２を参照。）、
（１７）化合物１７：　Ｎ－（５－｛４－［（１，１－ジオキシドチオモルホリノ）メチル］フェニル｝－［１，２，４］トリアゾロ［１，５－ａ］ピリジン－２－イル］シクロプロパンカルボキサミド　（例えば、特許文献２３を参照。）、
（１８）化合物１８：　Ｎ2－［２－（１Ｈ－ピロロ［２，３－ｂ］ピリジン－３－イル）ピリミジン－４－イル］－Ｎ－（２，２，２－トリフルオロエチル）－Ｄ－イソバリンアミド　（例えば、特許文献２４を参照。）。 Examples of the “compound having a JAK2 inhibitory action” include the following compounds.
(1) 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).
(2) Compound 2: N-tert-butyl-3- (5-methyl-2- {4- [2- (1-pyrrolidinyl) ethoxy] phenylamino} pyrimidin-4-ylamino) benzenesulfonamide (eg, patent (Ref. 4)
(3) Compound 3: 11- [2- (1-pyrrolidinyl) ethoxy] -14,19-dioxa-5,7,27-triazatetracyclo [19.3.1.1 (2,6). 1 (8,12)] heptacosa-1 (25), 2 (27), 3,5,8 (26), 9,11,16,21,23-decaene (see, for example, Patent Document 5),
(4) Compound 4: N-cyclopropyl-N ′-{3- [5- (morpholin-4-ylmethyl) -1H-benzimidazol-2-yl] -1H-pyrazol-4-yl} urea (for example, (See Patent Document 6)
(5) Compound 5: 3- (4-Chloro-2-fluorobenzyl) -2-methyl-N- (5-methyl-1H-pyrazol-3-yl) -8- (morpholin-4-ylmethyl) imidazo [ 1,2-b] pyridazine-6-amine (see, for example, Patent Document 7),
(6) Compound 6: N- (cyanomethyl) -4- {2- [4- (4-morpholinyl) phenylamino] pyrimidin-4-yl} benzamide (see, for example, Patent Document 8),
(7) Compound 7: (S) -5-chloro-N2- [1- (5-fluoropyrimidin-2-yl) ethyl] -N4- (5-methyl-1H-pyrazol-3-yl) pyrimidine-2 , 4-diamine (see, for example, Patent Document 9),
(8) Compound 8: N- [4- (2-{[4- (morpholin-4-yl) phenyl] amino} pyrimidin-4-yl) phenyl] -D-prolinamide (see, for example, Patent Document 10) ),
(9) Compound 9: N, N-dicyclopropyl-4- (1,5-dimethyl-1H-pyrazol-3-ylamino) -6-ethyl-1-methyl-1,6-dihydroimidazo [4,5 -D] pyrrolo [2,3-b] pyridine-7-carboxamide (see, for example, Patent Document 11),
(10) 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 (see, for example, Patent Document 12),
(11) Compound 11: 3- {4 (R) -methyl-3 (R)-[N-methyl-N- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino] piperidine-1 -Yl} -3-oxopropanenitrile (see, for example, Patent Document 13, Patent Document 14, and Patent Document 15),
(12) Compound 12: 14-methyl-20-oxa-5,7,14,27-tetraazatetracyclo [19.3.1.1 (2,6). 1 (8,12)] heptacosa-1 (25), 2 (27), 3,5,8 (26), 9,11,16,21,23-decaene (for example, Patent Document 16 and Patent Document 17) reference.),
(13) Compound 13: 2- {1- (ethylsulfonyl) -3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl] azetidine-3 -Yl} acetonitrile (see, for example, Patent Document 18),
(14) Compound 14: 9 (E) -15- [2- (1-pyrrolidinyl) ethoxy] -7,12,25-trioxa-19,21,24-triazatetracyclo [18.3.1.1 (2, 5). 1 (14, 18)] hexacosa-1 (24), 2, 4, 9, 14 (26), 15, 17, 20, 22-nonaene (see, for example, Patent Document 19),
(15) Compound 15: (2R, 3R) -3-[(2-{[4- (S-cyclopropylsulfonimidoyl) phenyl] amino} -5- (trifluoromethyl) pyrimidin-4-yl) oxy ] Butan-2-ol (see, for example, Patent Document 20 and Patent Document 21),
(16) Compound 16: (±)-(4-Fluorophenyl) {4-[(5-methyl-1H-pyrazol-3-yl) amino] quinazolin-2-yl} methanol (for example, see Patent Document 22) ),
(17) Compound 17: N- (5- {4-[(1,1-dioxidethiomorpholino) methyl] phenyl}-[1,2,4] triazolo [1,5-a] pyridin-2-yl Cyclopropanecarboxamide (see, for example, Patent Document 23),
(18) Compound 18: N 2 - [2- ( 1H- pyrrolo [2,3-b] pyridin-3-yl) pyrimidin-4-yl]-N-(2,2,2-trifluoroethyl) - D-Isovalinamide (see, for example, Patent Document 24).
　好ましい「ＪＡＫ２阻害作用を有する化合物」としては、例えば、化合物１０（（Ｓ）－Ｎ2－［１－（４－フルオロフェニル）エチル］－４－（１－メチル－１Ｈ－ピラゾール－４－イル）－Ｎ6－（ピラジン－２－イル）ピリジン－２，６－ジアミン）を挙げることができる。
Preferable “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).
　「医薬上許容される塩」としては、医薬上許容されるものであれば特に限定されないが、例えば、無機塩基との塩、有機塩基との塩、無機酸との塩、有機酸との塩を挙げることができる。無機塩基との塩としては、例えば、ナトリウム塩、カリウム塩などのアルカリ金属塩、カルシウム塩、マグネシウム塩などのアルカリ土類金属塩、アルミニウム塩、アンモニウム塩を挙げることができる。有機塩基との塩としては、例えば、トリメチルアミン、トリエチルアミン、ピリジン、ピコリン、２，６－ルチジン、エタノールアミン、ジエタノールアミン、トリエタノールアミン、シクロヘキシルアミン、ジシクロヘキシルアミン、Ｎ，Ｎ’－ジベンジルエチレンジアミンとの塩を挙げることができる。無機酸との塩としては、例えば、塩酸、臭化水素酸、硝酸、硫酸、リン酸との塩を挙げることができる。有機酸との塩としては、例えば、ギ酸、酢酸、トリフルオロ酢酸、フタル酸、フマル酸、シュウ酸、酒石酸、マレイン酸、クエン酸、コハク酸、リンゴ酸、メタンスルホン酸、ベンゼンスルホン酸、ｐ－トルエンスルホン酸との塩を挙げることができる。
　ＪＡＫ２阻害作用を有する化合物の医薬上許容される塩として、具体的には、化合物１のリン酸塩、化合物４の塩酸塩、化合物６の二塩酸塩、化合物１０のマレイン酸塩、化合物１１のクエン酸塩、化合物１２のクエン酸塩、化合物１６の臭化水素酸塩を挙げることができる。 The “pharmaceutically acceptable salt” is not particularly limited as long as it is pharmaceutically acceptable. For example, a salt with an inorganic base, a salt with an organic base, a salt with an inorganic acid, a salt with an organic acid Can be mentioned. 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. Examples of salts with organic bases include salts with trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, and N, N′-dibenzylethylenediamine. Can be mentioned. Examples of the salt with an inorganic acid include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, and phosphoric acid. Examples of 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.
As 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.
　「ＪＡＫ２阻害作用を有する化合物若しくはその医薬上許容される塩又はその溶媒和物」の“溶媒和物”としては、ＪＡＫ２阻害作用を有する化合物の溶媒和物や、ＪＡＫ２阻害作用を有する化合物の医薬上許容される塩の溶媒和物を挙げることができる。
　「化合物Ａ若しくはその医薬上許容される塩又はその溶媒和物」の“溶媒和物”としては、化合物Ａの溶媒和物や、化合物Ａの医薬上許容される塩の溶媒和物を挙げることができる。
　溶媒和物としては、例えば、水との溶媒和物（水和物）やアルコールやスルホキシド等の有機溶媒との溶媒和物を挙げることができ、具体的には、化合物Ａのジメチルスルホキシド和物を挙げることができる。
“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. Can do.
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.
　本発明として、化合物Ａ若しくはその医薬上許容される塩又はその溶媒和物、及びＪＡＫ２阻害作用を有する化合物若しくはその医薬上許容される塩又はその溶媒和物を含有する、骨髄線維症に伴う骨髄の線維化を抑制するための医薬組成物を挙げることができる。
　また、本発明として、化合物Ａ若しくはその医薬上許容される塩又はその溶媒和物を含有する医薬組成物、及びＪＡＫ２阻害作用を有する化合物若しくはその医薬上許容される塩又はその溶媒和物を含有する医薬組成物を組み合わせてなる、骨髄線維症に伴う骨髄の線維化を抑制するための組み合わせ医薬を挙げることができる。
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. And a combination medicine for suppressing bone marrow fibrosis associated with myelofibrosis, which is a combination of the pharmaceutical compositions.
　「化合物Ａ若しくはその医薬上許容される塩又はその溶媒和物、及びＪＡＫ２阻害作用を有する化合物若しくはその医薬上許容される塩又はその溶媒和物を含有する、骨髄線維症に伴う骨髄の線維化を抑制するための医薬組成物」とは、投与される一つの医薬中に、有効成分として、（ａ）骨髄線維症に伴う骨髄の線維化を抑制するために有効な量の化合物Ａ若しくはその医薬上許容される塩又はその溶媒和物、及び（ｂ）骨髄線維症を治療するために有効な量のＪＡＫ２阻害作用を有する化合物若しくはその医薬上許容される塩又はその溶媒和物を含有する、骨髄線維症に伴う骨髄の線維化を抑制するための医薬組成物を意味する。 "Fibrosis of bone marrow associated with myelofibrosis 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 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.
　「骨髄線維症を治療するために有効な量のＪＡＫ２阻害作用を有する化合物若しくはその医薬上許容される塩又はその溶媒和物」の有効な量としては、患者の体内に入った時に、例えば、骨髄線維症の主症状の１つである脾腫を縮小するために必要な量であり、例えば、年齢、体重、疾病の種類、程度等の患者の状態、投与経路を考慮した上で調製することが望ましいが、通常は、成人（体重約６０ｋｇ）に対して、ＪＡＫ２阻害作用を有する化合物若しくはその医薬上許容される塩又はその溶媒和物の有効成分量として、経口投与の場合、１日あたり、０．０１ｍｇ～５ｇ／成人の範囲内、好ましくは、１ｍｇ～５００ｍｇ／成人の範囲内が適当である。場合によっては、これ以下でも足りるし、また逆にこれ以上の用量を必要とすることもある。 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.
　有効成分として、化合物Ａ若しくはその医薬上許容される塩又はその溶媒和物、及びＪＡＫ２阻害作用を有する化合物若しくはその医薬上許容される塩又はその溶媒和物を含有する医薬組成物（例えば、配合剤）は、連日投与、または間歇的に投与しても良く、一日当たりの投与回数は、１回または２～３回に分けて行うことができる。 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 (for example, formulation The agent) may be administered daily or intermittently, and the number of administrations per day can be once or divided into 2 to 3 times.
　化合物Ａ若しくはその医薬上許容される塩又はその溶媒和物、及びＪＡＫ２阻害作用を有する化合物若しくはその医薬上許容される塩又はその溶媒和物を含有する医薬組成物は、例えば、骨髄線維症に伴う骨髄の線維化を抑制、脾腫を縮小する効果が期待できることから、骨髄線維症を治療するために使用し得る。
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.
　「化合物Ａ若しくはその医薬上許容される塩又はその溶媒和物を含有する医薬組成物、及びＪＡＫ２阻害作用を有する化合物若しくはその医薬上許容される塩又はその溶媒和物を含有する医薬組成物を組み合わせてなる、骨髄線維症に伴う骨髄の線維化を抑制するための組み合わせ医薬」とは、例えば、（ａ）有効成分として骨髄線維症に伴う骨髄の線維化を抑制するために有効な量の化合物Ａ若しくはその医薬上許容される塩又はその溶媒和物を含有する医薬組成物と、（ｂ）有効成分として骨髄線維症を治療するために有効な量のＪＡＫ２阻害作用を有する化合物若しくはその医薬上許容される塩又はその溶媒和物を含有する医薬組成物をひとまとまりの状態にした、骨髄線維症に伴う骨髄の線維化を抑制するための医薬を意味する。 “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. “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.
　化合物Ａ若しくはその医薬上許容される塩又はその溶媒和物を含有する医薬組成物とＪＡＫ２阻害作用を有する化合物若しくはその医薬上許容される塩又はその溶媒和物を含有する医薬組成物をひとまとまりの状態にしたものとしては、例えば、それぞれの医薬組成物を一式として揃えた状態である、キットの形態のものを挙げることができる。具体的なキットの形態としては、例えば、医薬組成物の製造段階において一連の投与スケジュールに従って特定の期間に相当する両医薬組成物を１つのシートにまとめて包装したブリスターパッケージ（例えば、ＰＴＰシート）、又は調剤又は処方段階において１回の使用ごとに両医薬組成物が同一包装に入れられた状態のものを挙げることができる。 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. As what was made into this state, the thing of the form of a kit which is the state which prepared each pharmaceutical composition as a set can be mentioned, for example. As 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. Or, in the preparation or prescription stage, both pharmaceutical compositions can be mentioned in the same package for each use.
　化合物Ａ若しくはその医薬上許容される塩又はその溶媒和物を含有する医薬組成物、及びＪＡＫ２阻害作用を有する化合物若しくはその医薬上許容される塩又はその溶媒和物を含有する医薬組成物を組み合わせてなる医薬は、例えば、骨髄線維症に伴う骨髄の線維化を抑制、脾腫を縮小する効果が期待できることから、骨髄線維症を治療するために使用し得る。
Combination of 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 For example, since the effect of suppressing the fibrosis of the bone marrow accompanying myelofibrosis and the effect of reducing the splenomegaly can be expected, the medicament as described above can be used to treat myelofibrosis.
　化合物Ａ若しくはその医薬上許容される塩又はその溶媒和物を含有する医薬組成物とＪＡＫ２阻害作用を有する化合物若しくはその医薬上許容される塩又はその溶媒和物を含有する医薬組成物を別々の医薬組成物として処方された場合、又は化合物Ａ若しくはその医薬上許容される塩又はその溶媒和物を含有する医薬組成物とＪＡＫ２阻害作用を有する化合物若しくはその医薬上許容される塩又はその溶媒和物を含有する医薬組成物を組み合わせてなる医薬を処方された場合には、それぞれの医薬組成物を同時に、又は逐次的に投与することができる。それぞれの医薬組成物を逐次的に投与する場合、例えば、それぞれの医薬組成物を異なる投与スケジュールで使用することもできる。また、一定の時間間隔をあけてそれぞれの医薬組成物を投与する場合や、一定の期間一方の医薬組成物を投与した後、他方の医薬組成物を投与する場合も含まれる。 Separately, 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.
　化合物Ａ若しくはその医薬上許容される塩又はその溶媒和物を含有する医薬組成物とＪＡＫ２阻害作用を有する化合物若しくはその医薬上許容される塩又はその溶媒和物を含有する医薬組成物とがそれぞれ別々の医薬組成物である場合、それぞれの医薬組成物は同じ剤形であっても、異なる剤型であっても構わない。また、それぞれの投与経路は同一であっても、異なっていてもよい。
A pharmaceutical composition 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, respectively. When they are separate pharmaceutical compositions, each pharmaceutical composition may be in the same dosage form or in different dosage forms. Moreover, each administration route may be the same or different.
　有効成分として、化合物Ａ若しくはその医薬上許容される塩又はその溶媒和物とＪＡＫ２阻害作用を有する化合物若しくはその医薬上許容される塩又はその溶媒和物を含有する医薬組成物（例えば、配合剤）、有効成分として化合物Ａ若しくはその医薬上許容される塩又はその溶媒和物を含有する医薬組成物、又は有効成分としてＪＡＫ２阻害作用を有する化合物若しくはその医薬上許容される塩又はその溶媒和物を含有する医薬組成物は、化合物Ａ若しくはその医薬上許容される塩又はその溶媒和物、及び／又はＪＡＫ２阻害作用を有する化合物若しくはその医薬上許容される塩又はその溶媒和物を、そのまま又は医薬的に許容される無毒性かつ不活性の担体中に、例えば、０．００１％～９９．５％、好ましくは、０．１％～９０％含有する医薬として、人を含む哺乳動物に投与される。
　上記担体としては、固形、半固形、又は液状の希釈剤、充填剤、及びその他の処方用の助剤一種以上が用いられる。 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 pharmaceutical composition containing Compound A or a pharmaceutically acceptable salt or solvate thereof as an active ingredient, or a compound having a JAK2 inhibitory action or an pharmaceutically acceptable salt or solvate thereof as an active ingredient Or a pharmaceutically acceptable salt or solvate thereof, and / or a compound having JAK2 inhibitory activity or a pharmaceutically acceptable salt or solvate thereof, as it is or In 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.
As the carrier, one or more solid, semi-solid, or liquid diluents, fillers, and other prescription auxiliary agents are used.
　本発明に係る医薬組成物は、固形又は液状の用量単位で、末剤、散剤、カプセル剤、錠剤、シロップ剤、懸濁剤、液剤、糖衣剤、顆粒剤、エリキシル剤、トローチ剤等の経口投与製剤、注射剤、軟膏剤、ローション剤、クリーム等の非経口投与製剤のいずれかの形態をもとることができる。徐放性製剤であってもよい。それらの中で、経口投与製剤が好ましい。 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.
　本発明に係る医薬組成物の製剤化は、公知の製剤技術を用いることにより行うことができるが、例えば、以下の方法を用いることにより行うことができる。
　末剤は、化合物Ａ若しくはその医薬上許容される塩又はその溶媒和物、及び／又はＪＡＫ２阻害作用を有する化合物若しくはその医薬上許容される塩又はその溶媒和物を適当な細かさにすることにより製造することができる。
　散剤は、化合物Ａ若しくはその医薬上許容される塩又はその溶媒和物、及び／又はＪＡＫ２阻害作用を有する化合物若しくはその医薬上許容される塩又はその溶媒和物を適当な細かさにし、次いで同様に細かくした医薬用担体、例えば、澱粉、マンニトールのような可食性炭水化物と混合することにより製造することができる。任意に風味剤、保存剤、分散剤、着色剤、香料等を添加することができる。
　カプセル剤は、まず上述したように粉末状となった末剤や散剤あるいは錠剤の項で述べるように顆粒化したものを、例えば、ゼラチンカプセルのようなカプセル外皮の中に充填することにより製造することができる。滑沢剤や流動化剤、例えば、コロイド状のシリカ、タルク、ステアリン酸マグネシウム、ステアリン酸カルシウム、固形のポリエチレングリコールを粉末状となった末剤や散剤と混合し、その後、充填操作を行うことにより製造することもできる。また、崩壊剤や可溶化剤、例えば、カルボキシメチルセルロース、カルボキシメチルセルロースカルシウム、低置換度ヒドロキシプロピルセルロース、クロスカルメロースナトリウム、カルボキシメチルスターチナトリウム、炭酸カルシウム、炭酸ナトリウムを添加することができる。さらに、化合物Ａ若しくはその医薬上許容される塩又はその溶媒和物、及び／又はＪＡＫ２阻害作用を有する化合物若しくはその医薬上許容される塩又はその溶媒和物の微粉末を植物油、ポリエチレングリコール、グリセリン、界面活性剤中に懸濁分散し、これをゼラチンシートで包んで軟カプセル剤とすることもできる。
　錠剤は、粉末化された化合物Ａ若しくはその医薬上許容される塩又はその溶媒和物、及び／又はＪＡＫ２阻害作用を有する化合物若しくはその医薬上許容される塩又はその溶媒和物に賦形剤を加えて粉末混合物を作り、顆粒化若しくはスラグ化し、次いで崩壊剤又は滑沢剤を加えた後、打錠することにより製造することができる。
　シロップ剤は、化合物Ａ若しくはその医薬上許容される塩又はその溶媒和物、及び／又はＪＡＫ２阻害作用を有する化合物若しくはその医薬上許容される塩又はその溶媒和物を適当な香味水溶液に溶解して製造することができる。
　エリキシル剤は、非毒性のアルコール性担体を用いることにより製造することができる。
　懸濁剤は、化合物Ａ若しくはその医薬上許容される塩又はその溶媒和物、及び／又はＪＡＫ２阻害作用を有する化合物若しくはその医薬上許容される塩又はその溶媒和物を非毒性担体中に分散させることにより製造することができる。必要に応じて、可溶化剤や乳化剤（例えば、エトキシ化されたイソステアリンアルコール類、ポリオキシエチレンソルビトールエステル類）、保存剤、風味付与剤（例えば、ペパーミント油、サッカリン）等を添加することができる。必要であれば、経口投与のための用量単位処方をマイクロカプセル化することができる。当該処方はまた、被覆をしたり、高分子・ワックス等中に埋め込んだりすることにより作用時間の延長や持続放出をもたらすこともできる。
　注射剤は、化合物Ａ若しくはその医薬上許容される塩又はその溶媒和物、及び／又はＪＡＫ２阻害作用を有する化合物若しくはその医薬上許容される塩又はその溶媒和物の一定量を、注射の目的に適合する非毒性の液状担体、例えば、水性又は油性の媒体に懸濁し又は溶解し、次いで当該懸濁液又は溶液を滅菌することにより製造することができる。注射剤を等張にするために非毒性の塩や塩溶液を添加することができる。また、安定剤、保存剤、乳化剤等を添加することもできる。
　軟膏剤は、例えば、化合物Ａ若しくはその医薬上許容される塩又はその溶媒和物、及び／又はＪＡＫ２阻害作用を有する化合物若しくはその医薬上許容される塩又はその溶媒和物と疎水性基剤や親水性基剤等の基剤とを混合することにより製造することができる。また、保存剤、酸化防止剤等を添加することもできる。
　ローション剤は、例えば、化合物Ａ若しくはその医薬上許容される塩又はその溶媒和物、及び／又はＪＡＫ２阻害作用を有する化合物若しくはその医薬上許容される塩又はその溶媒和物と溶剤、乳化剤、懸濁化剤等と上水や精製水等の水性の液体に加え、溶解又は分散させることにより製造することができる。また、保存剤等を添加することもできる。
　液剤、トローチ剤、エリキシル剤もまたその一定量が化合物Ａ若しくはその医薬上許容される塩又はその溶媒和物、及び／又はＪＡＫ２阻害作用を有する化合物若しくはその医薬上許容される塩又はその溶媒和物の一定量を含有するように用量単位形態にすることができる。
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.
For the powder, 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. Can be manufactured.
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. A flavoring agent, a preservative, a dispersing agent, a coloring agent, a fragrance | 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. Further, 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. Further, 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. In addition, 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. Can be manufactured.
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. Can be manufactured. If necessary, solubilizers and emulsifiers (for example, ethoxylated isostearic alcohols, polyoxyethylene sorbitol esters), preservatives, flavoring agents (for example, peppermint oil, saccharin) and the like can be added. . If necessary, 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. Can be prepared by suspending or dissolving in a non-toxic liquid carrier such as an aqueous or oily medium and then sterilizing the suspension or solution. Non-toxic salts and salt solutions can be added to make the injection isotonic. In addition, 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. It can be produced by dissolving or dispersing in addition to a turbidizing agent and an aqueous liquid such as clean water or purified water. A preservative or the like can also be added.
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.
　以下に試験例を掲げて本発明を更に詳しく説明するが、本発明はこれらのみに限定されるものではない。
　骨髄線維症マウスには、骨髄や脾臓の線維化、脾臓の腫大等を呈するＪＡＫ２Ｖ６１７Ｆトランスジェニックマウスを使用した（例えば、非特許文献７を参照）。本骨髄線維症マウス（４カ月齢、雌）に対しては、（Ａ）０．５％メチルセルロース溶液（和光純薬工業株式会社　ＣＡＴ．ＮＯ．１３８－０５０５２）、（Ｂ）５０ｍｇ／ｋｇの化合物１０のマレイン酸塩（特許文献１２に記載の方法で従って製造）を０．５％メチルセルロース溶液で希釈した投与液、（Ｃ）５ｍｇ／ｋｇの化合物Ａ（ＬＣ　Ｌａｂｏｒａｔｏｒｉｅｓ社製）を０．５％メチルセルロース溶液で希釈した投与液、（Ｄ）５０ｍｇ／ｋｇの化合物１０のマレイン酸塩と５ｍｇ／ｋｇの化合物Ａを０．５％メチルセルロース溶液で希釈した投与液を、それぞれ１日１回経口投与した。一方、野生型マウス（ＢＤＦ１マウス、４カ月齢、雌）に対しては、０．５％メチルセルロース溶液を経口投与した。それぞれのマウスに対し、３カ月間投与した後、安楽死させ、大腿骨、脛骨、脾臓、血漿を採取した。
Hereinafter, the present invention will be described in more detail with reference to test examples, but the present invention is not limited thereto.
As the myelofibrosis mouse, a JAK2V617F transgenic mouse exhibiting bone marrow and spleen fibrosis, spleen enlargement, etc. was used (see, for example, Non-Patent Document 7). For this myelofibrosis mouse (4 months old, female), (A) 0.5% methylcellulose solution (Wako Pure Chemical Industries, Ltd. CAT. No. 138-05052), (B) 50 mg / kg compound 10 maleate (manufactured according to the method described in Patent Document 12) diluted with 0.5% methylcellulose solution; (C) 5 mg / kg of compound A (LC Laboratories) 0.5% An administration solution diluted with a methylcellulose solution, (D) an administration solution obtained by diluting 50 mg / kg of Compound 10 maleate and 5 mg / kg of Compound A with a 0.5% methylcellulose solution was orally administered once a day. . On the other hand, 0.5% methylcellulose solution was orally administered to wild type mice (BDF1 mice, 4 months old, female). Each mouse was administered for 3 months, then euthanized, and femur, tibia, spleen and plasma were collected.
試験例１：　骨髄線維症マウスを用いた骨髄線維化抑制作用の検討
　薬物非投与の骨髄線維症マウス、化合物１０のマレイン酸塩を投与した骨髄線維症マウス、化合物Ａを投与した骨髄線維症マウス、及び化合物１０のマレイン酸塩と化合物Ａを投与した骨髄線維症マウスより採取した大腿骨及び脛骨をホルマリン固定後パラフィン包埋した（各群５～６匹）。パラフィン切片を用いて鍍銀染色を行い、線維成分を染色した。代表的な大腿骨の写真を、一例ずつ図１～４に示す。
　この結果から、化合物Ａを投与した骨髄線維症マウス、又はＪＡＫ２阻害剤である化合物１０のマレイン酸塩と化合物Ａを投与した骨髄線維症マウスは、薬物非投与の骨髄線維症マウスと比較して、骨髄の線維化が抑制されていることが明らかである。
 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.
From this result, 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.
試験例２：骨髄線維症マウスを用いた脾臓重量の検討
　薬物非投与の野生型マウス、薬物非投与の骨髄線維症マウス、化合物１０のマレイン酸塩を投与した骨髄線維症マウス、化合物Ａを投与した骨髄線維症マウス、及び化合物１０のマレイン酸塩と化合物Ａを投与した骨髄線維症マウスより採取した脾臓の重量を測定した（各群１０～１６匹）。その結果を図６に示す。
　この結果から、ＪＡＫ２阻害作用である化合物１０のマレイン酸と化合物Ａを投与した骨髄線維症マウスは、薬物非投与の骨髄線維症マウスと比較して、脾臓の重量が軽いことが明らかである。
 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.
試験例３：骨髄線維症マウスを用いた脾臓の線維化抑制作用の検討
　薬物非投与の骨髄線維症マウス、化合物１０のマレイン酸塩を投与した骨髄線維症マウス、化合物Ａを投与した骨髄線維症マウス、及び化合物１０のマレイン酸塩と化合物Ａを投与した骨髄線維症マウスより採取した脾臓をホルマリン固定後パラフィン包埋した（各群５～６匹）。パラフィン切片を用いて鍍銀染色を行い、線維成分を染色した。代表的な写真を、一例ずつ図７～図１０に示す。
　この結果から、化合物Ａを投与した骨髄線維症マウス、又はＪＡＫ２阻害剤である化合物１０のマレイン酸塩と化合物Ａを投与した骨髄線維症マウスは、薬物非投与の骨髄線維症マウスと比較して、脾臓の線維化が抑制されていることが明らかである。
 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.
From this result, 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.
試験例４：骨髄線維症マウスを用いた脾臓機能の検討
　薬物非投与の骨髄線維症マウス、化合物１０のマレイン酸塩を投与した骨髄線維症マウス、化合物Ａを投与した骨髄線維症マウス、及び化合物１０のマレイン酸塩と化合物Ａを投与した骨髄線維症マウスより採取した脾臓をホルマリン固定後パラフィン包埋した（各群５～６匹）。パラフィン切片を用いてヘマトキシリン・エオジン染色を行った。代表的な写真を、一例ずつ図１１～図１４に示す。
　この結果から、ＪＡＫ２阻害剤である化合物１０のマレイン酸塩と化合物Ａを投与した骨髄線維症マウスは、薬物非投与の骨髄線維症マウスと比較して、脾臓機能が改善していることが明らかである。 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.
From this result, it is clear that myelofibrosis mice administered with maleate of compound 10 which is a JAK2 inhibitor and compound A have improved spleen function compared with non-drug-administered myelofibrosis mice. It is.

Claims (13)

  1. Ｎ－［（２Ｒ）－２，３－ジヒドロキシプロポキシ］－３，４－ジフルオロ－２－［（２－フルオロ－４－ヨードフェニル）アミノ］ベンズアミド若しくはその医薬上許容される塩又はその溶媒和物を含有する、骨髄線維症に伴う骨髄の線維化を抑制するための医薬組成物。 N-[(2R) -2,3-dihydroxypropoxy] -3,4-difluoro-2-[(2-fluoro-4-iodophenyl) amino] benzamide or a pharmaceutically acceptable salt thereof or a solvate thereof A pharmaceutical composition for inhibiting bone marrow fibrosis associated with myelofibrosis.
  2. 骨髄線維症の治療剤である、請求項１に記載の医薬組成物。 The pharmaceutical composition according to claim 1, which is a therapeutic agent for myelofibrosis.
  3. ＪＡＫ２阻害作用を有する化合物若しくはその医薬上許容される塩又はその溶媒和物を含有する医薬組成物と併用されることを特徴とする、請求項１又は２のいずれかに記載の医薬組成物。 3. The pharmaceutical composition according to claim 1, which is used in combination with a pharmaceutical composition comprising a compound having a JAK2 inhibitory action or a pharmaceutically acceptable salt thereof or a solvate thereof.
  4. ＪＡＫ２阻害作用を有する化合物が（Ｓ）－Ｎ2－［１－（４－フルオロフェニル）エチル］－４－（１－メチル－１Ｈ－ピラゾール－４－イル）－Ｎ6－（ピラジン－２－イル）ピリジン－２，６－ジアミンである、請求項３に記載の医薬組成物。 The compound having JAK2 inhibitory action is (S) -N 2- [1- (4-fluorophenyl) ethyl] -4- (1-methyl-1H-pyrazol-4-yl) -N 6- (pyrazine-2- The pharmaceutical composition according to claim 3, which is yl) pyridine-2,6-diamine.
  5. Ｎ－［（２Ｒ）－２，３－ジヒドロキシプロポキシ］－３，４－ジフルオロ－２－［（２－フルオロ－４－ヨードフェニル）アミノ］ベンズアミド若しくはその医薬上許容される塩又はその溶媒和物、及びＪＡＫ２阻害作用を有する化合物若しくはその医薬上許容される塩又はその溶媒和物を含有する、骨髄線維症に伴う骨髄の線維化を抑制するための医薬組成物。 N-[(2R) -2,3-dihydroxypropoxy] -3,4-difluoro-2-[(2-fluoro-4-iodophenyl) amino] benzamide or a pharmaceutically acceptable salt thereof or a solvate thereof And a pharmaceutical composition for suppressing bone marrow fibrosis associated with myelofibrosis, comprising a compound having a JAK2 inhibitory action or a pharmaceutically acceptable salt thereof or a solvate thereof.
  6. 骨髄線維症の治療剤である、請求項５に記載の医薬組成物。 The pharmaceutical composition according to claim 5, which is a therapeutic agent for myelofibrosis.
  7. ＪＡＫ２阻害作用を有する化合物が（Ｓ）－Ｎ2－［１－（４－フルオロフェニル）エチル］－４－（１－メチル－１Ｈ－ピラゾール－４－イル）－Ｎ6－（ピラジン－２－イル）ピリジン－２，６－ジアミンである、請求項５又は６のいずれかに記載の医薬組成物。 The compound having JAK2 inhibitory action is (S) -N 2- [1- (4-fluorophenyl) ethyl] -4- (1-methyl-1H-pyrazol-4-yl) -N 6- (pyrazine-2- Yl) The pharmaceutical composition according to any one of claims 5 and 6, which is pyridine-2,6-diamine.
  8. Ｎ－［（２Ｒ）－２，３－ジヒドロキシプロポキシ］－３，４－ジフルオロ－２－［（２－フルオロ－４－ヨードフェニル）アミノ］ベンズアミド若しくはその医薬上許容される塩又はその溶媒和物を含有する医薬組成物、及びＪＡＫ２阻害作用を有する化合物若しくはその医薬上許容される塩又はその溶媒和物を含有する医薬組成物を組み合わせてなる、骨髄線維症に伴う骨髄の線維化を抑制するための組み合わせ医薬。 N-[(2R) -2,3-dihydroxypropoxy] -3,4-difluoro-2-[(2-fluoro-4-iodophenyl) amino] benzamide or a pharmaceutically acceptable salt thereof or a solvate thereof Which suppresses bone marrow fibrosis associated with myelofibrosis, which comprises a combination of a pharmaceutical composition containing a compound and a pharmaceutical composition containing a compound having a JAK2 inhibitory action or a pharmaceutically acceptable salt or solvate thereof Combination medicine for.
  9. 骨髄線維症を治療するための、請求項８に記載の組み合わせ医薬。 The combination medicine according to claim 8 for treating myelofibrosis.
  10. ＪＡＫ２阻害作用を有する化合物が（Ｓ）－Ｎ2－［１－（４－フルオロフェニル）エチル］－４－（１－メチル－１Ｈ－ピラゾール－４－イル）－Ｎ6－（ピラジン－２－イル）ピリジン－２，６－ジアミンである、請求項８又は９のいずれかに記載の組み合わせ医薬。 The compound having JAK2 inhibitory action is (S) -N 2- [1- (4-fluorophenyl) ethyl] -4- (1-methyl-1H-pyrazol-4-yl) -N 6- (pyrazine-2- 10) The combined pharmaceutical according to any one of claims 8 and 9, which is yl) pyridine-2,6-diamine.
  11. （Ｓ）－Ｎ2－［１－（４－フルオロフェニル）エチル］－４－（１－メチル－１Ｈ－ピラゾール－４－イル）－Ｎ6－（ピラジン－２－イル）ピリジン－２，６－ジアミンと併用されることを特徴とする、
    Ｎ－［（２Ｒ）－２，３－ジヒドロキシプロポキシ］－３，４－ジフルオロ－２－［（２－フルオロ－４－ヨードフェニル）アミノ］ベンズアミド若しくはその医薬上許容される塩又はその溶媒和物を含有する、骨髄線維症を治療するための医薬組成物。     (S) -N 2- [1- (4-Fluorophenyl) ethyl] -4- (1-methyl-1H-pyrazol-4-yl) -N 6- (pyrazin-2-yl) pyridin-2,6 -Characterized in that it is used in combination with a diamine,
    N-[(2R) -2,3-dihydroxypropoxy] -3,4-difluoro-2-[(2-fluoro-4-iodophenyl) amino] benzamide or a pharmaceutically acceptable salt thereof or a solvate thereof A pharmaceutical composition for treating myelofibrosis, comprising:
  12. Ｎ－［（２Ｒ）－２，３－ジヒドロキシプロポキシ］－３，４－ジフルオロ－２－［（２－フルオロ－４－ヨードフェニル）アミノ］ベンズアミド若しくはその医薬上許容される塩又はその溶媒和物、及び（Ｓ）－Ｎ2－［１－（４－フルオロフェニル）エチル］－４－（１－メチル－１Ｈ－ピラゾール－４－イル）－Ｎ6－（ピラジン－２－イル）ピリジン－２，６－ジアミン若しくはその医薬上許容される塩又はその溶媒和物を含有する、骨髄線維症を治療するための医薬組成物。 N-[(2R) -2,3-dihydroxypropoxy] -3,4-difluoro-2-[(2-fluoro-4-iodophenyl) amino] benzamide or a pharmaceutically acceptable salt thereof or a solvate thereof And (S) -N 2- [1- (4-fluorophenyl) ethyl] -4- (1-methyl-1H-pyrazol-4-yl) -N 6- (pyrazin-2-yl) pyridine-2 , 6-diamine or a pharmaceutically acceptable salt thereof or a solvate thereof, a pharmaceutical composition for treating myelofibrosis.
  13. Ｎ－［（２Ｒ）－２，３－ジヒドロキシプロポキシ］－３，４－ジフルオロ－２－［（２－フルオロ－４－ヨードフェニル）アミノ］ベンズアミド若しくはその医薬上許容される塩又はその溶媒和物を含有する医薬組成物、及び（Ｓ）－Ｎ2－［１－（４－フルオロフェニル）エチル］－４－（１－メチル－１Ｈ－ピラゾール－４－イル）－Ｎ6－（ピラジン－２－イル）ピリジン－２，６－ジアミン若しくはその医薬上許容される塩又はその溶媒和物を含有する医薬組成物を組み合わせてなる、骨髄線維症を治療するための組み合わせ医薬。 N-[(2R) -2,3-dihydroxypropoxy] -3,4-difluoro-2-[(2-fluoro-4-iodophenyl) amino] benzamide or a pharmaceutically acceptable salt thereof or a solvate thereof And (S) -N 2- [1- (4-fluorophenyl) ethyl] -4- (1-methyl-1H-pyrazol-4-yl) -N 6- (pyrazine-2) -Yl) A combination drug for treating myelofibrosis, comprising a combination of a pharmaceutical composition containing pyridine-2,6-diamine or a pharmaceutically acceptable salt thereof or a solvate thereof.
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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006061712A2 (en) * 2004-12-10 2006-06-15 Pfizer Inc. Use of mek inhibitors in treating abnormal cell growth
WO2010090290A1 (en) * 2009-02-06 2010-08-12 日本新薬株式会社 Aminopyrazine derivative and medicine

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006061712A2 (en) * 2004-12-10 2006-06-15 Pfizer Inc. Use of mek inhibitors in treating abnormal cell growth
WO2010090290A1 (en) * 2009-02-06 2010-08-12 日本新薬株式会社 Aminopyrazine derivative and medicine

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
CHANG, T. ET AL.: "Sustained MEK inhibition abrogates myeloproliferative disease in Nfl mutant mice", THE JOURNAL OF CLINICAL INVESTIGATION, vol. 123, no. 1, 2013, pages 335 - 339 *
FISKUS, W. ET AL.: "Role of additional novel therapies in myeloproliferative neoplasms", HEMATOLOGY/ONCOLOGY CLINICS OF NORTH AMERICA, vol. 26, no. 5, 2012, pages 959 - 980, XP008174538, DOI: doi:10.1016/j.hoc.2012.07.001 *
KATSUTO TAKENAKA ET AL.: "Kotsuzui Fuzen Shokogun (Toppatsusei Zoketsu Shogai): Shindan to Chiryo no Shinpo III. Shindan to Chiryo 6. Kotsuzui Sen'isho", JAPANESE SOCIETY OF INTERNAL MEDICINE, vol. 101, no. 7, 2012, pages 1969 - 1976 *
LYUBYNSKA, N. ET AL.: "A MEK Inhibitor Abrogates Myeloproliferative Disease in Kras Mutant Mice", SCIENCE TRANSLATIONAL MEDICINE, vol. 3, no. 76, 2011, pages 1 - 7 *
MIYUKI TSUTSUI ET AL.: "Kotsuzui Zoshokusei Shuyo no Chiryo-JAK2 Sogaiyaku-The 6th", BIO CLINICA, vol. 29, no. 1, January 2014 (2014-01-01), pages 97 - 101 *
SHIDE, K. ET AL.: "Therapies Targeting the MAPK Pathway Improve Bone Marrow (BM) Fibrosis Induced By JAK2V617F", BLOOD, vol. 124, no. 21, December 2014 (2014-12-01), pages 162 *

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