WO2023175932A1 - Agent thérapeutique pour myélofibrose à haut risque - Google Patents

Agent thérapeutique pour myélofibrose à haut risque Download PDF

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Publication number
WO2023175932A1
WO2023175932A1 PCT/JP2022/012705 JP2022012705W WO2023175932A1 WO 2023175932 A1 WO2023175932 A1 WO 2023175932A1 JP 2022012705 W JP2022012705 W JP 2022012705W WO 2023175932 A1 WO2023175932 A1 WO 2023175932A1
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Prior art keywords
fluorophenyl
pyrazin
ylamino
ethylamino
ethyl
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PCT/JP2022/012705
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English (en)
Japanese (ja)
Inventor
朋典 宇野
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日本新薬株式会社
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Priority to PCT/JP2022/012705 priority Critical patent/WO2023175932A1/fr
Priority to PCT/JP2023/010686 priority patent/WO2023176972A1/fr
Publication of WO2023175932A1 publication Critical patent/WO2023175932A1/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
    • A61K31/33—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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid

Definitions

  • the present invention is based on the general formula [1]: [wherein R 1 , R 2 , R 3 , R 4 , R 5 , and X are as described herein]
  • the present invention relates to a novel therapeutic agent for high-risk myelofibrosis, which contains the compound represented by or a pharmaceutically acceptable salt thereof as an active ingredient.
  • Myelofibrosis is a disease with extensive bone marrow fibrosis and often extramedullary hematopoiesis (mainly in the spleen), which can be primary or secondary to malignant and benign hematological disorders.
  • myelofibrosis in addition to symptoms of anemia and splenomegaly, some patients exhibit symptoms of general malaise, weight loss, fever, or splenic infarction in the later stages (Non-Patent Document 1).
  • the International Prognostic Scoring System (IPSS) for myelodysplastic syndromes is used for newly diagnosed primary myelofibrosis
  • the Dynamic International Prognostic Scoring System (IPSS) for myelodysplastic syndromes (IPSS) is used for newly diagnosed primary myelofibrosis.
  • nostic Scoring System; DIPSS can be used to predict progression to chronic myeloid leukemia (Non-Patent Document 1).
  • DIPSS-plus has been proposed, which takes into account platelet count of 100,000/ ⁇ L or less, chromosomes with poor prognosis, and blood transfusion dependence to DIPSS (Non-Patent Document 2).
  • Myelofibrosis is classified into low risk, intermediate-1 risk, intermediate-2 risk, and high risk based on the International Prognostic Scoring System.
  • ruxolitinib which nonspecifically inhibits the JAK pathway, is the first-line treatment for advanced primary myelofibrosis.
  • the main adverse effects of ruxolitinib are anemia and thrombocytopenia (Non-Patent Document 1).
  • Ruxolitinib is a JAK1/2 inhibitor. Ruxolitinib is used to treat adult patients with intermediate-risk or high-risk primary or secondary (post-polycythemia vera or post-essential thrombocythemia) myelofibrosis (MF), with baseline platelet count It is used only for patients with 50,000/ ⁇ L or more (Non-Patent Document 3).
  • Fedratinib is a JAK2 selective inhibitor.
  • Fedratinib is used to treat adult patients with intermediate- or high-risk primary or secondary (post-polycythemia vera or post-essential thrombocythemia) myelofibrosis (MF), but the baseline platelet count It is used only for patients with 50,000/ ⁇ L or more (Non-Patent Document 4).
  • the main purpose of the present invention is to provide a novel therapeutic agent for high-risk myelofibrosis.
  • the present invention provides a compound represented by the following general formula [1] (hereinafter referred to as the "compound of the present invention") or a pharmaceutically acceptable compound thereof, which is either the following (I) or (II).
  • Examples include therapeutic agents for high-risk myelofibrosis that contain salts as active ingredients.
  • (I) represents CH or N.
  • R 1 represents halogen.
  • R2 is (1)H, (2) Halogen, (3) Cyano, (4) a group represented by the following general formula [2],
  • R C , R D , R E are the same or different and represent (a) H, or (b) alkyl optionally substituted with hydroxy or alkoxy. , or two groups among R C , R D , and R E are combined with adjacent C, and the remaining group becomes H to represent a saturated heterocyclic group containing one N.
  • Such a group represents a saturated heterocyclic group containing one N.
  • Saturated heterocyclic groups may be substituted with alkylsulfonyl), (5) a group represented by the following general formula [3],
  • R F and R G are the same or different, and (a) H, (b) hydroxy, amino, dialkylamino, saturated cyclic amino group, alkylcarbonylamino, alkyl alkyl optionally substituted with one or two groups selected from the group consisting of sulfonylamino, aryl, heteroaryl optionally substituted with alkyl, tetrahydrofuranyl, and carbamoyl, (c) alkylcarbonyl, ( d) represents a heteroaryl optionally substituted with alkylsulfonyl, (e) carbamoyl, or (f) alkyl, or R F and R G taken together with the adjacent N form a saturated cyclic amino group.
  • Such saturated cyclic amino group is selected from the group consisting of (a) halogen, (b) cyano, (c) hydroxy, (d) hydroxy, alkoxy, amino, alkoxycarbonylamino, alkylsulfonylamino, and alkylcarbonylamino.
  • Alkyl optionally substituted with one or two groups, (e) cycloalkyl, (f) haloalkyl, (g) alkoxy, (h) oxo, (i) represented by the following general formula [4]
  • R H represents alkyl or aryl
  • j a group represented by the following general formula [5],
  • R I and R J are the same or different and represent H, alkyl, carbamoyl, alkylcarbonyl, or alkylsulfonyl.
  • R K is alkyl, hydroxy, amino, alkylamino, dialkylamino, cycloalkylamino, (cycloalkyl)alkylamino, (hydroxyalkyl)amino, (alkoxyalkyl) (representing amino, alkoxy, alkylsulfonylamino, or a saturated cyclic amino group), and (l) a saturated cyclic amino group optionally substituted with hydroxy. or may form a spiro bond with a group represented by the following general formula [7A] or [7B].
  • R L is a saturated cyclic amino group optionally substituted with (a) alkyl, (b) hydroxy, (c) alkoxy, (d) alkyl or alkylsulfonyl. or (e) may be substituted with one or two groups selected from the group consisting of alkyl, cycloalkyl, (cycloalkyl)alkyl, aralkyl, haloalkyl, dialkylaminoalkyl, alkoxyalkyl, and hydroxyalkyl. represents amino), (7) a group represented by the following general formula [9],
  • R M , R N , R O are the same or different and represent H, halogen, cyano, alkoxy, carbamoyl, sulfamoyl, monoalkylaminosulfonyl, or alkylsulfonyl) or two groups of R M , R N , R O together represent methylenedioxy), (8) -OR P (R P is alkyl optionally substituted with a group selected from the group consisting of hydroxy, dialkylamino, alkoxy, tetrahydrofuranyl, and cycloalkyl, or optionally substituted with hydroxy) or (9) cyano, halogen, hydroxy, alkoxy, alkylcarbonyl, carbamoyl, alkyl, cycloalkyl, (cycloalkyl)alkyl, aralkyl. represents a heteroaryl optionally substituted with one or two groups selected from the group consisting of ,
  • R A represents a group represented by the following general formula [10]. (In the formula, * has the same meaning as above.
  • R B is substituted with one or two groups selected from the group consisting of (a) alkyl, cycloalkyl, (cycloalkyl)alkyl, and alkoxyalkyl. represents an optionally saturated amino group, (b) alkoxy, (c) hydroxy, or (d) a saturated cyclic amino group.)
  • R 1 represents halogen.
  • R 2 represents H.
  • R 3 represents H or hydroxy.
  • R 4 represents H or alkyl.
  • R 5 represents H or alkyl.
  • R F1 and R G1 are the same or different, (a) H, (b) hydroxy, amino, dialkylamino, saturated cyclic amino group, alkylcarbonylamino, alkyl alkyl optionally substituted with one or two groups selected from the group consisting of sulfonylamino, aryl, heteroaryl optionally substituted with alkyl, tetrahydrofuranyl, and carbamoyl, (c) alkylcarbonyl, ( d) represents a heteroaryl optionally substituted with alkylsulfonyl, (e) carbamoyl, or (f) alkyl, or R F1 and R G1 together with the adjacent N form a saturated cyclic amino group.
  • Such saturated cyclic amino group is selected from the group consisting of (a) halogen, (b) cyano, (c) hydroxy, (d) hydroxy, alkoxy, amino, alkoxycarbonylamino, alkylsulfonylamino, and alkylcarbonylamino.
  • the group to be (In the formula, * and R H have the same meanings as above.), (j) a group represented by the following general formula [5], (In the formula, *, R I and R J have the same meanings as above.), (k) a group represented by the following general formula [6], (In the formula, * and R K have the same meanings as above.) and (l) a saturated cyclic amino group optionally substituted with hydroxy. You can leave it there.
  • R P1 represents alkyl optionally substituted with a group selected from the group consisting of hydroxy, dialkylamino, alkoxy, tetrahydrofuranyl, and cycloalkyl), or ( 5) Substituted with one or two groups selected from the group consisting of cyano, halogen, hydroxy, alkoxy, alkylcarbonyl, carbamoyl, alkyl, cycloalkyl, (cycloalkyl)alkyl, aralkyl, hydroxycarbonyl, and alkoxyalkyl. optional heteroaryl.
  • X is -CR A
  • R A is a group represented by the following general formula [10], (In the formula, * and R B have the same meanings as above.)
  • R2 is H.
  • X is CH
  • R2 is (1) A group represented by the following general formula [11], (In the formula, *, R F1 and R G1 have the same meanings as above.) (2) a group represented by the following general formula [8], (In the formula, * and R L have the same meanings as above.) (3) a group represented by the following general formula [9], (In the formula, *, R M , R N , and R O have the same meanings as above.) (4) -OR P1 (wherein R P1 has the same meaning as above), or (5) cyano, halogen, hydroxy, alkoxy, alkylcarbonyl, carbamoyl, alkyl, cycloalkyl, (cycloalkyl)alkyl, More preferred are compounds of the present invention or pharmaceutically acceptable salts thereof, which are heteroaryls optionally substituted with one or two groups selected from the group consisting of aralkyl, hydroxycarbonyl, and alkoxyalkyl.
  • the compound of the present invention or a pharmaceutically acceptable salt thereof is useful as a pharmaceutical.
  • halogen examples include fluorine, chlorine, bromine, and iodine.
  • alkyl examples include linear or branched ones having 1 to 8 carbon atoms, specifically methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, Mention may be made of tert-butyl, n-pentyl, isopentyl, n-hexyl, isohexyl, n-heptyl, isoheptyl, n-octyl. Among these, those having 1 to 6 carbon atoms are preferred, and those having 1 to 3 carbon atoms are more preferred.
  • alkylsulfonyl "alkylcarbonylamino", “hydroxyalkyl", “(cycloalkyl)alkyl", “alkoxyalkyl", “alkylamino”, “(hydroxyalkyl)amino", “(alkoxyalkyl)amino", "(alkoxyalkyl)amino", The alkyl moiety of "dialkylamino”, “dialkylaminoalkyl", “(cycloalkyl)alkylamino", "alkylcarbonyl", “alkylcarbonylamino", “alkylsulfonyl", “alkylsulfonylamino", “monoalkylaminosulfonyl”
  • alkyl group include the same ones as the above-mentioned "alkyl".
  • haloalkyl examples include straight-chain or branched alkyl having 1 to 8 carbon atoms and substituted with one or more halogen atoms at any substitutable position.
  • alkyl moiety and halogen moiety of “haloalkyl” include those similar to the above-mentioned “alkyl” and “halogen", respectively.
  • cycloalkyl examples include those having 3 to 8 carbon atoms, specifically cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like.
  • cycloalkyl moiety of "(cycloalkyl)alkyl”, “cycloalkylamino", and “(cycloalkyl)alkylamino” include those similar to the above-mentioned "cycloalkyl”.
  • Alkoxy includes, for example, a linear or branched chain having 1 to 8 carbon atoms, specifically methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy , t-butoxy, n-pentyloxy, n-hexyloxy, n-heptyloxy, and n-octyloxy.
  • alkoxyalkyl examples include those similar to the above “alkoxy”.
  • aryl examples include those having 6 to 10 carbon atoms, such as phenyl, 1-naphthyl, and 2-naphthyl. Among them, phenyl is preferred.
  • Alkyl includes, for example, straight-chain or branched alkyl having 1 to 8 carbon atoms substituted at any position where aryl having 6 to 10 carbon atoms can be substituted, such as benzyl, phenylethyl ( For example, 1-phenylethyl, 2-phenylethyl), phenylpropyl (1-phenylpropyl, 2-phenylpropyl, 3-phenylpropyl, etc.), naphthylmethyl (for example, 1-naphthylmethyl, 2-naphthylmethyl, etc.) can be mentioned.
  • saturated cyclic amino group includes, for example, a 4- to 7-membered saturated cyclic amino group that may have one O or S as a ring constituent atom, and has one or two N atoms, and specifically Examples include 1-azetidinyl, 1-pyrrolidinyl, 1-imidazolidinyl, piperidino, 1-piperazinyl, 1-tetrahydropyrimidinyl, morpholino, thiomorpholino, and 1-homopiperazinyl.
  • the "saturated heterocyclic group containing one N" includes, for example, a 5- or 6-membered saturated heterocyclic group containing one N as a ring constituent atom, specifically, for example, 2-pyrrolidinyl , 3-pyrrolidinyl, 2-piperidinyl, 3-piperidinyl, and 4-piperidinyl.
  • “Saturated cyclic group that may contain one O” includes, for example, a 5- or 6-membered saturated cyclic group that may contain one O as a ring constituent atom, specifically can include, for example, cyclopentyl, cyclohexyl, tetrahydrofuranyl, and tetrahydropyranyl.
  • Heteroaryl is, for example, a 5- or 6-membered one having 1 to 4 N, O, or S as ring constituent atoms, specifically, for example, furyl (e.g., 2-furyl, 3-furyl, -furyl), thienyl (e.g. 2-thienyl, 3-thienyl), pyrrolyl (e.g. 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), imidazolyl (e.g. 1-imidazolyl, 2-imidazolyl, 4-imidazolyl) , pyrazolyl (e.g. 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl), triazolyl (e.g.
  • pyridyl e.g. 2-pyridyl, 3-pyridyl, 4-pyridyl
  • pyridazinyl e.g. 3-pyridazinyl, 4-pyridazinyl
  • pyrimidinyl e.g. 2 -pyr
  • tetrahydrofuranyl examples include 2-tetrahydrofuranyl and 3-hydrofuranyl.
  • tetrahydropyranyl examples include 2-tetrahydropyranyl, 3-tetrahydropyranyl, and 4-tetrahydropyranyl.
  • the compounds of the present invention can be produced from known compounds or easily synthesizable intermediates, for example, according to the following method.
  • the reaction is generally carried out after the raw material is protected in advance with an appropriate protecting group by a known method. After the reaction, the protecting group can be removed by a known method.
  • R2 is halogen (R 1 and R 5 have the same meanings as above.
  • X 1 represents CH or N.
  • Hal 1 and Hal 2 are the same or different and represent halogen.)
  • This reaction is a condensation reaction of compound [12] and compound [13] using a palladium catalyst, and therefore can be carried out by a method known per se as a condensation reaction.
  • Usable solvents are not particularly limited as long as they do not participate in the reaction, but include, for example, hydrocarbons such as toluene and xylene, ethers such as 1,4-dioxane and tetrahydrofuran, N,N-dimethylformamide, N, Examples include amides such as N-dimethylacetamide and N-methyl-2-pyrrolidone, and mixed solvents thereof.
  • the reaction is carried out in the presence of a base at a temperature of 20°C to 200°C.
  • palladium catalysts examples include tris(dibenzylideneacetone)(chloroform)dipalladium(0), tris(dibenzylideneacetone)dipalladium(0), and palladium(II) acetate.
  • the amount of palladium catalyst that can be used is suitably within the range of 0.001 to 0.1 mole per mole of aryl halide.
  • Examples of the palladium catalyst ligands that can be used include 1,1'-bis(diphenylphosphino)ferrocene, 4,5-bis(diphenylphosphino)-9,9'-dimethylxanthene, and 2-dicyclohexylphosphino- 2',4',6'-triisopropylbiphenyl, ( ⁇ )-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl, 2-(di-t-butylphosphino)biphenyl, bis Examples include [2-(diphenylphosphino)phenyl]ether and tri-t-butylphosphine.
  • Examples of bases that can be used include sodium t-butoxide, tripotassium phosphate, and cesium carbonate.
  • the reaction time varies depending on the type of raw materials used, reaction temperature, etc., but is usually within the range of 10 minutes to 24 hours.
  • Compound [12] which is a raw material compound, is produced according to a known method (Bioorg. Med. Chem. Lett., 14, 2004, 4249-4252, Org. Lett., 6, 2004, 3671-3674, etc.) be able to.
  • R P is substituted with a group selected from the group consisting of hydroxy, dialkylamino, alkoxy, tetrahydrofuranyl, and cycloalkyl; represents a saturated cyclic group which may be substituted with alkyl or hydroxy and which may contain one O.
  • This reaction is carried out by a condensation reaction between compound [1a] and alcohol compound [14] using a palladium catalyst.
  • Usable solvents are not particularly limited as long as they do not participate in the reaction, but include, for example, hydrocarbons such as toluene and xylene, ethers such as 1,4-dioxane and tetrahydrofuran, N,N-dimethylformamide, N, Examples include amides such as N-dimethylacetamide and N-methyl-2-pyrrolidone, and mixed solvents thereof.
  • This reaction can be carried out in the presence of a base at a temperature of 20°C to 200°C.
  • the palladium catalyst examples include tris(dibenzylideneacetone)(chloroform)dipalladium(0), tris(dibenzylideneacetone)dipalladium(0), and palladium(II) acetate.
  • the amount of palladium catalyst that can be used is suitably within the range of 0.001 to 0.1 mole per mole of aryl halide.
  • Examples of palladium catalyst ligands that can be used include 4,5-bis(diphenylphosphino)-9,9'-dimethylxanthene, 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, ( ⁇ )-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl, 2-(di-t-butylphosphino)biphenyl, bis[2-(diphenylphosphino)phenyl]ether be able to.
  • Examples of bases that can be used include sodium t-butoxide and tripotassium phosphate.
  • the reaction time varies depending on the type of raw materials used, reaction temperature, etc., but is usually within the range of 10 minutes to 24 hours.
  • This reaction is a condensation reaction of compound [15] and compound [13] using a palladium catalyst, and can be carried out by the same method as Production Method 1 above.
  • Compound [15] which is a raw material compound, can be produced, for example, according to the following method.
  • Compound [18] can be produced by reacting compound [16] and alcohol compound [17] in a suitable solvent in the presence of a base at a temperature of -20°C to 100°C.
  • bases that can be used include sodium hydride and sodium hydroxide.
  • Usable solvents are not particularly limited as long as they do not participate in the reaction, but include, for example, hydrocarbons such as toluene and xylene, ethers such as 1,4-dioxane and tetrahydrofuran, N,N-dimethylformamide, N, Examples include amides such as N-dimethylacetamide and N-methyl-2-pyrrolidone, water, and a mixed solvent thereof.
  • the reaction time varies depending on the type of raw materials used and the reaction temperature, but is usually suitable for 30 minutes to 24 hours.
  • This reaction is a condensation reaction of compound [18] and compound [19] using a palladium catalyst, and therefore, it can be carried out by a method known per se as a condensation reaction.
  • Usable solvents are not particularly limited as long as they do not participate in the reaction, but include, for example, hydrocarbons such as toluene and xylene, ethers such as 1,4-dioxane and tetrahydrofuran, N,N-dimethylformamide, N, Examples include amides such as N-dimethylacetamide and N-methyl-2-pyrrolidone, and mixed solvents thereof.
  • This reaction can be carried out in the presence of a base at a temperature of 20°C to 200°C.
  • palladium catalysts examples include tris(dibenzylideneacetone)(chloroform)dipalladium(0), tris(dibenzylideneacetone)dipalladium(0), and palladium(II) acetate.
  • the amount of palladium catalyst that can be used is suitably within the range of 0.001 to 0.1 mole per mole of aryl halide.
  • Examples of palladium catalyst ligands that can be used include 4,5-bis(diphenylphosphino)-9,9'-dimethylxanthene, ( ⁇ )-2,2'-bis(diphenylphosphino)-1,1 '-binaphthyl, 2-(di-t-butylphosphino)biphenyl, bis[2-(diphenylphosphino)phenyl]ether, and tri-t-butylphosphine.
  • bases that can be used include sodium t-butoxide, tripotassium phosphate, and cesium carbonate.
  • the reaction time varies depending on the type of raw materials used, reaction temperature, etc., but is usually within the range of 10 minutes to 24 hours.
  • R 2 is a group represented by the following general formula [9], (In the formula, R M , R N , R O , * have the same meanings as above.), or Even if substituted with one or two groups selected from the group consisting of cyano, halogen, hydroxy, alkoxy, alkylcarbonyl, carbamoyl, alkyl, cycloalkyl, (cycloalkyl)alkyl, aralkyl, hydroxycarbonyl and alkoxyalkyl For good heteroaryls (limited to those where the bond comes out from C)
  • Manufacturing method 3-1 (X 1 , R 1 , R 5 , and Hal 2 have the same meanings as above.
  • R 6 and R 7 both represent hydroxy, or R 6 and R 7 together represent -OC( CH 3 ) 2 -C(CH 3 ) 2 -O-, -O-(CH 2 ) 3 -O-, or -O-CH 2 -C(CH 3 ) 2 -CH 2 -O-.
  • R 8 is a group represented by the following general formula [9], (In the formula, R M , R N , R O , * have the same meanings as above.), or Even if substituted with one or two groups selected from the group consisting of cyano, halogen, hydroxy, alkoxy, alkylcarbonyl, carbamoyl, alkyl, cycloalkyl, (cycloalkyl)alkyl, aralkyl, hydroxycarbonyl and alkoxyalkyl Represents a good heteroaryl (limited to those where the bond originates from C). )
  • This reaction is a cross-coupling reaction using compound [1a] and organic boron compound [20], and can be carried out by a method known per se.
  • This reaction can be carried out, for example, in the presence of a palladium catalyst and a base in a suitable solvent at 20 to 200°C.
  • palladium catalysts that can be used include tetrakis(triphenylphosphine)palladium, dichlorobis(triphenylphosphine)palladium, and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride-dichloromethane complex. I can do it.
  • the amount of palladium catalyst that can be used is suitably within the range of 0.001 to 0.1 mole per mole of aryl halide.
  • the reaction solvent that can be used is not particularly limited as long as it does not participate in the reaction, but examples include ethers such as tetrahydrofuran, 1,4-dioxane, and 1,2-dimethoxyethane, alcohols such as methanol and ethanol, N, Examples include amides such as N-dimethylformamide and N,N-dimethylacetamide, hydrocarbons such as benzene and toluene, water, and mixed solvents thereof. Furthermore, examples of bases that can be used include sodium hydroxide, potassium carbonate, and sodium carbonate.
  • the reaction time varies depending on the type of raw materials used and the reaction temperature, but is usually within the range of 30 minutes to 24 hours.
  • This reaction is a condensation reaction of compound [21] and compound [13] using a palladium catalyst, and is carried out by a method known per se.
  • Solvents that can be used are not particularly limited as long as they do not participate in the reaction, but include, for example, hydrocarbons such as toluene and xylene, ethers such as 1,4-dioxane and tetrahydrofuran, N,N-dimethylformamide, N,N Amides such as -dimethylacetamide and N-methyl-2-pyrrolidone, and mixed solvents thereof can be mentioned.
  • This reaction can be carried out in the presence of a base at a temperature of 20°C to 200°C.
  • palladium catalysts examples include tris(dibenzylideneacetone)(chloroform)dipalladium(0), tris(dibenzylideneacetone)dipalladium(0), and palladium(II) acetate.
  • the amount of palladium catalyst that can be used is suitably within the range of 0.001 to 0.1 mole per mole of aryl halide.
  • Examples of the palladium catalyst ligands that can be used include 1,1'-bis(diphenylphosphino)ferrocene, 4,5-bis(diphenylphosphino)-9,9'-dimethylxanthene, and 2-dicyclohexylphosphino- 2',4',6'-triisopropylbiphenyl, ( ⁇ )-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl, 2-(di-t-butylphosphino)biphenyl, bis Examples include [2-(diphenylphosphino)phenyl]ether and tri-t-butylphosphine.
  • Examples of bases that can be used include sodium t-butoxide, tripotassium phosphate, and cesium carbonate.
  • the reaction time varies depending on the type of raw materials used, reaction temperature, etc., but is usually within the range of 10 minutes to 24 hours.
  • Compound [21] which is a raw material compound, can be produced, for example, according to the following three methods.
  • This reaction is a cross-coupling reaction using compound [22] and organic boron compound [20], and can be carried out by a method known per se.
  • This reaction can be carried out, for example, in the presence of a palladium catalyst and a base in a suitable solvent at a temperature of 20 to 200°C.
  • palladium catalysts that can be used include tetrakis(triphenylphosphine)palladium, dichlorobis(triphenylphosphine)palladium, and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride-dichloromethane complex. I can do it.
  • the amount of palladium catalyst that can be used is suitably within the range of 0.001 to 0.1 mole per mole of aryl halide.
  • the reaction solvent that can be used is not particularly limited as long as it does not participate in the reaction, but examples include ethers such as tetrahydrofuran, 1,4-dioxane, and 1,2-dimethoxyethane, alcohols such as methanol and ethanol, N, Examples include amides such as N-dimethylformamide and N,N-dimethylacetamide, hydrocarbons such as benzene and toluene, water, and mixed solvents thereof. Examples of bases that can be used include sodium hydroxide, potassium carbonate, and sodium carbonate.
  • the reaction time varies depending on the type of raw materials used and the reaction temperature, but is usually within the range of 30 minutes to 24 hours.
  • This reaction is a condensation reaction of compound [23] and compound [19] using a palladium catalyst, and therefore can be carried out by a method known per se as a condensation reaction.
  • Usable solvents are not particularly limited as long as they do not participate in the reaction, but include, for example, hydrocarbons such as toluene and xylene, ethers such as 1,4-dioxane and tetrahydrofuran, N,N-dimethylformamide, N, Examples include amides such as N-dimethylacetamide and N-methyl-2-pyrrolidone, and mixed solvents thereof.
  • This reaction can be carried out in the presence of a base at a temperature of 20°C to 200°C.
  • palladium catalysts examples include tris(dibenzylideneacetone)(chloroform)dipalladium(0), tris(dibenzylideneacetone)dipalladium(0), and palladium(II) acetate.
  • the amount of palladium catalyst that can be used is suitably within the range of 0.001 to 0.1 mole per mole of aryl halide.
  • Examples of palladium catalyst ligands that can be used include 4,5-bis(diphenylphosphino)-9,9'-dimethylxanthene, ( ⁇ )-2,2'-bis(diphenylphosphino)-1,1 '-binaphthyl, 2-(di-t-butylphosphino)biphenyl, bis[2-(diphenylphosphino)phenyl]ether, and tri-t-butylphosphine.
  • bases that can be used include sodium t-butoxide, tripotassium phosphate, and cesium carbonate.
  • the reaction time varies depending on the type of raw materials used, reaction temperature, etc., but is usually within the range of 10 minutes to 24 hours.
  • This reaction is a cross-coupling reaction using compound [12] and organic tin compound [24], and can be carried out by a method known per se.
  • This reaction can be carried out, for example, in the presence of a palladium catalyst in a suitable solvent at 20 to 200°C.
  • palladium catalysts examples include tetrakis(triphenylphosphine)palladium, dichlorobis(triphenylphosphine)palladium, 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride-dichloromethane complex, and palladium acetate. can be mentioned.
  • the amount of palladium catalyst that can be used is suitably within the range of 0.001 to 0.1 mole per mole of aryl halide.
  • the reaction solvent that can be used is not particularly limited as long as it does not participate in the reaction, but examples include ethers such as tetrahydrofuran, 1,4-dioxane, and 1,2-dimethoxyethane, N,N-dimethylformamide, N,N -Amides such as dimethylacetamide; hydrocarbons such as benzene and toluene; and mixed solvents thereof. It is also possible to add additives such as copper oxide and silver oxide.
  • the reaction time varies depending on the type of raw materials used and the reaction temperature, but is usually within the range of 1 to 24 hours.
  • This reaction is a cross-coupling reaction using compound [12] and organic boron compound [20], and can be carried out by a method known per se.
  • This reaction can be carried out, for example, in the presence of a palladium catalyst and a base in a suitable solvent at a temperature of 20 to 200°C.
  • palladium catalysts that can be used include tetrakis(triphenylphosphine)palladium, dichlorobis(triphenylphosphine)palladium, and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride-dichloromethane complex. I can do it.
  • the amount of palladium catalyst that can be used is suitably within the range of 0.001 to 0.1 mole per mole of aryl halide.
  • the reaction solvent that can be used is not particularly limited as long as it does not participate in the reaction, but examples include ethers such as tetrahydrofuran, 1,4-dioxane, and 1,2-dimethoxyethane, alcohols such as methanol and ethanol, N, Examples include amides such as N-dimethylformamide and N,N-dimethylacetamide, hydrocarbons such as benzene and toluene, water, and mixed solvents thereof. Examples of bases that can be used include sodium hydroxide, potassium carbonate, and sodium carbonate.
  • the reaction time varies depending on the type of raw materials used and the reaction temperature, but is usually within the range of 30 minutes to 24 hours.
  • R 2 is a group represented by the following general formula [3] (In the formula, R F and R G have the same meanings as above.)
  • Manufacturing method 4-1 (X 1 , R 1 , R 5 , and Hal 2 are as defined above.
  • R 12 represents a group represented by the following general formula [3].
  • This reaction is a cross-coupling reaction using compound [1a] and compound [25], and can be carried out by a method known per se.
  • Usable solvents are not particularly limited as long as they do not participate in the reaction, but include, for example, hydrocarbons such as toluene and xylene, ethers such as 1,4-dioxane and tetrahydrofuran, N,N-dimethylformamide, N, Examples include amides such as N-dimethylacetamide and N-methyl-2-pyrrolidone, and mixed solvents thereof.
  • This reaction can be carried out, for example, in the presence of a palladium catalyst and a base in a suitable solvent at a temperature of 20 to 200°C.
  • palladium catalysts examples include tris(dibenzylideneacetone)(chloroform)dipalladium(0), tris(dibenzylideneacetone)dipalladium(0), and palladium(II) acetate.
  • the amount of palladium catalyst that can be used is suitably within the range of 0.001 to 0.1 mole per mole of aryl halide.
  • Examples of the palladium catalyst ligands that can be used include 1,1'-bis(diphenylphosphino)ferrocene, 4,5-bis(diphenylphosphino)-9,9'-dimethylxanthene, and 2-dicyclohexylphosphino- 2',4',6'-triisopropylbiphenyl, ( ⁇ )-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl, 2-(di-t-butylphosphino)biphenyl, bis Examples include [2-(diphenylphosphino)phenyl]ether and tri-t-butylphosphine.
  • bases that can be used include sodium t-butoxide, tripotassium phosphate, and cesium carbonate.
  • the reaction time varies depending on the type of raw materials used and the reaction temperature, but is usually within the range of 30 minutes to 24 hours.
  • This reaction is a condensation reaction of compound [26] and compound [13] using a palladium catalyst, and can be carried out by a method known per se.
  • Usable solvents are not particularly limited as long as they do not participate in the reaction, but include, for example, hydrocarbons such as toluene and xylene, ethers such as 1,4-dioxane and tetrahydrofuran, N,N-dimethylformamide, N, Examples include amides such as N-dimethylacetamide and N-methyl-2-pyrrolidone, and mixed solvents thereof.
  • This reaction can be carried out in the presence of a base at a temperature of 20°C to 200°C.
  • palladium catalysts examples include tris(dibenzylideneacetone)(chloroform)dipalladium(0), tris(dibenzylideneacetone)dipalladium(0), and palladium(II) acetate.
  • the amount of palladium catalyst that can be used is suitably within the range of 0.001 to 0.1 mole per mole of aryl halide.
  • Examples of the palladium catalyst ligands that can be used include 1,1'-bis(diphenylphosphino)ferrocene, 4,5-bis(diphenylphosphino)-9,9'-dimethylxanthene, and 2-dicyclohexylphosphino- 2',4',6'-triisopropylbiphenyl, ( ⁇ )-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl, 2-(di-t-butylphosphino)biphenyl, bis Examples include [2-(diphenylphosphino)phenyl]ether and tri-t-butylphosphine.
  • Examples of bases that can be used include sodium t-butoxide, tripotassium phosphate, and cesium carbonate.
  • the reaction time varies depending on the type of raw materials used, reaction temperature, etc., but is usually within the range of 10 minutes to 24 hours.
  • Compound [26] which is a raw material compound, can be produced, for example, according to the following two methods. (X 1 , R 1 , R 12 , Hal 1 and Hal 2 have the same meanings as above.)
  • Method a Compound [26] can be produced by reacting compound [12] and compound [25] in a suitable solvent in the presence of a base at a temperature in the range of 20°C to 200°C.
  • bases include pyridine, triethylamine, N,N-diisopropylethylamine, potassium carbonate, and sodium hydrogen carbonate.
  • Usable solvents are not particularly limited as long as they do not participate in the reaction, but include alcohols such as 1-butanol and 2-methoxyethanol, ethers such as tetrahydrofuran and 1,4-dioxane, N,N-dimethylformamide, Examples include amides such as N,N-dimethylacetamide, hydrocarbons such as benzene and toluene, acetonitrile, and mixed solvents thereof.
  • the reaction time varies depending on the type of raw materials used and the reaction temperature, but is usually within the range of 1 to 24 hours.
  • Method b Compound [26] is a condensation reaction of compound [12] and compound [25] using a palladium catalyst, and can be carried out by a method known per se.
  • the solvent that can be used is not particularly limited as long as it does not participate in the reaction, but examples include hydrocarbons such as toluene and xylene, ethers such as 1,4-dioxane and tetrahydrofuran, and mixed solvents thereof. can.
  • This reaction can be carried out in the presence of a base at a temperature of 20°C to 200°C.
  • palladium catalysts examples include tris(dibenzylideneacetone)(chloroform)dipalladium(0), tris(dibenzylideneacetone)dipalladium(0), and palladium(II) acetate.
  • the amount of palladium catalyst that can be used is suitably within the range of 0.001 to 0.1 mol per 1 mol of aryl halide.
  • Examples of the palladium catalyst ligands that can be used include 1,1'-bis(diphenylphosphino)ferrocene, 4,5-bis(diphenylphosphino)-9,9'-dimethylxanthene, and 2-dicyclohexylphosphino- 2',4',6'-triisopropylbiphenyl, ( ⁇ )-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl, 2-(di-t-butylphosphino)biphenyl, bis Examples include [2-(diphenylphosphino)phenyl]ether and tri-t-butylphosphine.
  • Examples of bases that can be used include sodium t-butoxide, tripotassium phosphate, and cesium carbonate.
  • the reaction time varies depending on the type of raw materials used, reaction temperature, etc., but is usually within the range of 10 minutes to 24 hours.
  • R2 is one or two groups selected from the group consisting of cyano, halogen, hydroxy, alkoxy, alkylcarbonyl, carbamoyl, alkyl, cycloalkyl, (cycloalkyl)alkyl, aralkyl, hydroxycarbonyl, and alkoxyalkyl.
  • X 1 , R 1 , R 5 , and Hal 1 are as defined above.
  • R 13 is cyano, halogen, hydroxy, alkoxy, alkylcarbonyl, carbamoyl, alkyl, cycloalkyl, (cycloalkyl)alkyl, aralkyl, Represents a heteroaryl optionally substituted with one or two groups selected from the group consisting of hydroxycarbonyl and alkoxyalkyl (limited to those in which the bond originates from N).
  • This reaction is a condensation reaction of compound [27] and compound [13] using a palladium catalyst, and can be carried out by the same method as the production method 4-2 above.
  • Compound [27] which is a raw material compound, can be produced according to the following method.
  • This reaction is a cross-coupling reaction using compound [12] and compound [28], and can be carried out by a method known per se.
  • This reaction can be carried out, for example, in the presence or absence of a copper catalyst in a suitable solvent at a temperature of 20 to 200°C.
  • copper catalysts that can be used include copper iodide and copper acetate.
  • the amount of copper catalyst that can be used is suitably within the range of 0.01 to 0.2 mol per 1 mol of the aryl halide.
  • examples of copper ligands include trans-N,N'-dimethylcyclohexane-1,2-diamine, trans-1,2-cyclohexanediamine, and 1,10-phenanthroline.
  • the reaction solvent that can be used is not particularly limited as long as it does not participate in the reaction, but examples include ethers such as tetrahydrofuran, 1,4-dioxane, and 1,2-dimethoxyethane, alcohols such as methanol and ethanol, N, Examples include amides such as N-dimethylformamide and N,N-dimethylacetamide, hydrocarbons such as benzene and toluene, and mixed solvents thereof. Examples of bases that can be used include tripotassium phosphate, potassium carbonate, sodium carbonate, and cesium carbonate.
  • the reaction time varies depending on the type of raw materials used and the reaction temperature, but is usually within the range of 30 minutes to 24 hours.
  • R 2 is alkoxycarbonyl (X 1 , R 1 , R 5 , and Hal 1 have the same meanings as above.
  • R 14 represents alkyl.
  • This reaction is a condensation reaction of compound [29] and compound [13] using a palladium catalyst, and can be carried out in the same manner as the production method 4-2 above.
  • Compound [29] which is a raw material compound, can be produced according to the following method. (X 1 , R 1 , R 14 , Hal 1 and Hal 3 have the same meanings as above.)
  • This reaction is a condensation reaction of compound [30] and compound [19] using a palladium catalyst, and can be carried out in the same manner as step 2 of the method for producing compound [15], which is the raw material compound.
  • This reaction is a hydrolysis reaction of compound [1f], and can be carried out by a method known per se.
  • Compound [1g] can usually be produced by hydrolyzing compound [1f] in the presence of an acid or a base.
  • acids used in this reaction include inorganic acids such as hydrochloric acid and sulfuric acid
  • bases include inorganic bases such as sodium hydroxide and potassium hydroxide.
  • the reaction solvent that can be used in this reaction include alcohols such as methanol and ethanol, ethers such as tetrahydrofuran and 1,4-dioxane, water, and mixed solvents thereof.
  • the reaction temperature is 0°C to 100°C, and the reaction time is usually 30 minutes to 24 hours.
  • R 2 is (a) a saturated cyclic amino group optionally substituted with alkyl or alkylsulfonyl, or (b) alkyl, cycloalkyl, (cycloalkyl)alkyl, aralkyl, haloalkyl, dialkylaminoalkyl, alkoxyalkyl
  • aminocarbonyl optionally substituted with one or two groups selected from the group consisting of , and hydroxyalkyl
  • X 1 , R 1 , and R 5 are as defined above.
  • R 15 and R 16 are the same or different, and are H, alkyl, cycloalkyl, (cycloalkyl)alkyl, aralkyl, haloalkyl, dialkylaminoalkyl, Represents alkoxyalkyl or hydroxyalkyl, or together with adjacent N represents a saturated cyclic amino group.Such a saturated cyclic amino group may be substituted with alkyl or alkylsulfonyl.)
  • This reaction is a condensation reaction between compound [1g] and compound [31], and can be carried out by a method known per se as a condensation reaction.
  • Compound [1h] can be synthesized by reacting the carboxylic acid represented by compound [1g] or its reactive derivative with compound [31].
  • Examples of reactive derivatives of compound [1g] include those commonly used in amide condensation formation reactions, such as acid halides (e.g., acid chloride, acid bromide), mixed acid anhydrides, imidazolides, activated amides, etc. .
  • the reaction can be carried out at -20 to 100°C using a condensing agent in the presence or absence of a base.
  • condensing agents that can be used in this reaction include 1,1'-oxalyldiimidazole, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, dicyclohexylcarbodiimide, diethyl cyanophosphonate, O-(benzotriazole)
  • condensing agents include 1,1'-oxalyldiimidazole, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, dicyclohexylcarbodiimide, diethyl cyanophosphonate, O-(benzotriazole)
  • examples include 1H-benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate.
  • bases that can be used in this reaction include organic bases such as triethylamine, N,N-diisopropylethylamine, N,N-dimethylaniline, pyridine, and 1,8-diazabicyclo[5,4,0]-7-undecene. can be mentioned.
  • the solvent that can be used is not particularly limited as long as it does not participate in the reaction, but examples include ethers such as tetrahydrofuran, 1,4-dioxane, and diethyl ether, N,N-dimethylformamide, and N,N-dimethylacetamide.
  • Examples include amides, nitriles such as acetonitrile and propionitrile, hydrocarbons such as benzene and toluene, halogenated hydrocarbons such as chloroform and methylene chloride, and mixed solvents thereof. Additionally, additives can be used if necessary. Examples of additives that can be used include 1-hydroxybenzotriazole and 1-hydroxy-7-azabenzotriazole.
  • the reaction time varies depending on the type of raw materials used, reaction temperature, etc., but is usually within the range of 10 minutes to 24 hours.
  • the appropriate amount of compound [31] and condensing agent to be used is, for example, in the range of 1 to 3 moles per 1 mole of compound [1 g].
  • R 2 is H
  • a saturated heterocyclic group containing one N that may be substituted with alkylcarbonyl, alkylsulfonyl, or alkyl that may be substituted with hydroxy or alkoxy
  • X 1 , R 1 , R 5 , and Hal 1 have the same meanings as above.
  • R 17 is a saturated heterocyclic group containing one N that may be substituted with H, alkylcarbonyl, or alkylsulfonyl, or represents alkyl which may be substituted with hydroxy or alkoxy
  • This reaction is a condensation reaction of compound [32] and compound [13] using a palladium catalyst, and can be carried out by the same method as Production Method 1 above.
  • This reaction is a cyanation reaction of compound [1a], and can be carried out by a method known per se.
  • This reaction can be carried out, for example, in the presence or absence of a palladium catalyst with a cyano compound in a suitable solvent at a temperature of 20 to 200°C, using a microwave if necessary.
  • palladium catalysts that can be used include tetrakis(triphenylphosphine)palladium, 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride-dichloromethane complex, tris(dibenzylideneacetone)dipalladium(0 ) can be mentioned.
  • the amount of palladium catalyst that can be used is suitably within the range of 0.001 to 0.1 mole per mole of aryl halide.
  • a palladium ligand 4,5-bis(diphenylphosphino)-9,9'-dimethylxanthene, 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, 2-dicyclohexyl Phosphino-2',6'-dimethoxybiphenyl and the like can be used.
  • Cyano compounds that can be used include copper(I) cyanide, zinc(II) cyanide, potassium cyanide, and sodium cyanide.
  • Usable reaction solvents are not particularly limited as long as they do not participate in the reaction, but include, for example, ethers such as tetrahydrofuran and 1,4-dioxane, alcohols such as methanol and ethanol, N,N-dimethylformamide, N, Examples include amides such as N-dimethylacetamide and N-methyl-2-pyrrolidone, hydrocarbons such as benzene and toluene, dimethyl sulfoxide, water, and mixed solvents thereof.
  • the reaction time varies depending on the type of raw materials used and the reaction temperature, but is usually within the range of 30 minutes to 24 hours.
  • This reaction is a condensation reaction of compound [33] and compound [13] using a palladium catalyst, and can be carried out in the same manner as the production method 4-2 above.
  • Compound [33] which is a raw material compound, can be produced according to the following method. (R 1 , R 18 , Hal 1 and Hal 3 have the same meanings as above.)
  • This reaction is a condensation reaction of Compound [34] and Compound [19] using a palladium catalyst, and can be carried out in the same manner as in Step 2 of Method A in Production Method 3-2.
  • This reaction is a hydrolysis reaction of compound [1k], and can be carried out by the same method as Production Method 7 above.
  • R A is a group represented by the following general formula [35] (In the formula, * has the same meaning as above.
  • R 19 and R 20 are the same or different and represent H, alkyl, cycloalkyl, (cycloalkyl)alkyl, or alkoxyalkyl, or adjacent N Together with, represents a saturated cyclic amino group.)
  • This reaction is a condensation reaction between compound [1j] and compound [36], and can be carried out by the same method as Production Method 8 above.
  • R4 is alkyl (X, R 1 , R 2 , R 3 , R 5 and Hal 1 have the same meanings as above.
  • R 21 represents alkyl.
  • This reaction is a condensation reaction of compound [37] and compound [13] using a palladium catalyst, and can be carried out by the same method as the production method 4-2 above.
  • Compound [37] which is a raw material compound, can be produced according to the following method.
  • (X 1 , R 1 , R 2 , R 21 , and Hal 1 have the same meanings as above.
  • Hal 4 represents halogen.)
  • This step can be produced by reacting compound [38] and compound [39] in an appropriate solvent in the presence of a base at 20°C to 200°C, using a microwave if necessary.
  • a base examples include sodium hydride, lithium diisopropylamide, n-butyllithium, and the like.
  • the solvent that can be used is not particularly limited as long as it does not participate in the reaction, but examples include ethers such as tetrahydrofuran and 1,4-dioxane, amides such as N,N-dimethylformamide and N,N-dimethylacetamide, Examples include hydrocarbons such as benzene and toluene, acetonitrile, and mixed solvents thereof.
  • the reaction time varies depending on the type of raw materials used and the reaction temperature, but is usually within the range of 10 minutes to 24 hours.
  • This reaction is a condensation reaction of compound [40] and compound [13] using a palladium catalyst, and can be carried out by the same method as Production Method 1 above.
  • a base that can be used in this reaction sodium t-butoxide is suitable.
  • Compound [40] which is a raw material compound, can be produced according to the following method.
  • (X 1 , R 1 , R 2 , Hal 1 and Hal 3 have the same meanings as above.)
  • Compound [42] can be produced according to a known method (J. Org. Chem., 65, 2000, 9059-9068, etc.).
  • This step is a condensation reaction of compound [42] and compound [43] using a palladium catalyst, and can be carried out, for example, by the same method as Production Method 1 above.
  • the compound of the present invention can be used as a medicine as it is, but it can also be used in the form of a pharmaceutically acceptable salt by a known method.
  • Such salts include salts of mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, citric acid, tartaric acid, maleic acid, succinic acid, fumaric acid, p-toluenesulfonic acid, benzenesulfonic acid, Examples include salts of organic acids such as methanesulfonic acid.
  • the hydrochloride of the compound of the present invention can be obtained by dissolving the compound of the present invention in an alcoholic solution, ethyl acetate solution, or diethyl ether solution of hydrogen chloride.
  • optical isomers can be obtained, for example, by using optically active acids (tartaric acid, dibenzoyltartaric acid, mandelic acid, 10-camphorsulfonic acid, etc.) using the basicity of the racemic body obtained as described above. It can be optically resolved by the method described above, or it can be produced using a previously prepared optically active compound as a raw material. In addition, it can also be produced by optical resolution using a chiral column or asymmetric synthesis.
  • optically active acids tartaric acid, dibenzoyltartaric acid, mandelic acid, 10-camphorsulfonic acid, etc.
  • the compound of the present invention has geometric isomers or tautomers, not only one of the isomers but also a mixture thereof is included in the compound of the present invention.
  • the compound of the present invention or a pharmaceutically acceptable salt thereof is a JAK selective inhibitor, has a therapeutic effect on myelofibrosis, and is useful as a medicine, as shown in the test examples below.
  • the myelofibrosis is, for example, primary myelofibrosis, myelofibrosis after polycythemia vera, or myelofibrosis after essential thrombocythemia, preferably primary myelofibrosis.
  • the risk classification of myelofibrosis can be classified into low risk, intermediate-1 risk, intermediate-2 risk, and high risk.
  • the risk classification of myelofibrosis can be performed, for example, based on the International Prognostic Scoring System for PMF (IPSS).
  • International prognostic scoring systems include, for example, IPSS, Dynamic IPSS (DIPSS), Age-adjusted DIPSS (aaDIPSS), and DIPSS-plus.
  • the high-risk myelofibrosis is, for example, at least one risk group of myelofibrosis selected from the group consisting of intermediate-2 risk and high risk based on the International Prognostic Scoring System. Yes, preferably intermediate-2 risk and/or high risk myelofibrosis based on the International Prognostic Scoring System, more preferably intermediate-2 risk based on the Dynamic International Prognostic Scoring System (DIPSS). 2 risk and/or high risk myelofibrosis.
  • DIPSS Dynamic International Prognostic Scoring System
  • the high-risk myelofibrosis is, for example, myelofibrosis of at least one risk group selected from the group consisting of intermediate-2 risk and high risk, preferably intermediate-2 risk. and/or high risk myelofibrosis.
  • the patient with high-risk myelofibrosis has bone marrow in at least one risk group selected from the group consisting of intermediate-2 risk and high risk, for example, based on the International Prognostic Scoring System.
  • a patient with fibrosis preferably a patient with intermediate-2 risk and/or high risk myelofibrosis based on the International Prognostic Scoring System, more preferably a patient with myelofibrosis based on the Dynamic International Prognostic Scoring System ( Patients with intermediate-2 risk and/or high risk myelofibrosis based on DIPSS).
  • the high-risk myelofibrosis patient is, for example, a myelofibrosis patient in at least one risk group selected from the group consisting of intermediate-2 risk and high risk, and preferably Patients with intermediate-2 risk and/or high risk myelofibrosis.
  • platelet counts in patients with myelofibrosis can be measured by methods commonly used in the art.
  • the platelet count of a patient with myelofibrosis can be measured before, during, or after administration of the compound of the present invention or a pharmaceutically acceptable salt thereof.
  • measurements can be taken twice (at least 7 days apart) prior to administration, and every 28 days per cycle during administration.
  • the platelet count of a patient with high-risk myelofibrosis is not particularly limited as long as the compound of the present invention or a pharmaceutically acceptable salt thereof can be administered, but the upper limit is, for example, 100,000/ less than ⁇ L, less than 90,000/ ⁇ L, less than 80,000/ ⁇ L, less than 70,000/ ⁇ L, less than 60,000/ ⁇ L, less than 50,000/ ⁇ L, or less than 40,000/ ⁇ L, and the lower limit is: 10,000/ ⁇ L or more, 20,000/ ⁇ L or more, 30,000/ ⁇ L or more, 40,000/ ⁇ L or more, 50,000/ ⁇ L or more, 60,000/ ⁇ L or more, 70,000/ ⁇ L or more, 80 ,000/ ⁇ L or more, and 90,000/ ⁇ L or more.
  • the upper limit is, for example, 100,000/ less than ⁇ L, less than 90,000/ ⁇ L, less than 80,000/ ⁇ L, less than 70,000/ ⁇ L, less than 60,000/ ⁇ L, less than 50,000/ ⁇ L, or less than
  • the upper and lower platelet count limits for high-risk myelofibrosis patients can be used in combination.
  • the platelet count of patients with high-risk myelofibrosis is, for example, 10,000/ ⁇ L or more and less than 60,000/ ⁇ L, 30,000/ ⁇ L or more and less than 50,000/ ⁇ L, and 30,000/ ⁇ L or more and less than 50,000/ ⁇ L. / ⁇ L or more and less than 60,000/ ⁇ L, 40,000/ ⁇ L or more and less than 60,000/ ⁇ L, 60,000/ ⁇ L or more and less than 100,000/ ⁇ L, preferably 10,000/ ⁇ L or more. - less than 60,000/ ⁇ L, or 30,000/ ⁇ L or more and less than 50,000/ ⁇ L, more preferably 30,000/ ⁇ L or more and less than 50,000/ ⁇ L.
  • the spleen volume of a patient with myelofibrosis can be calculated by measuring spleen size by methods commonly used in the art, such as MRI or CT.
  • the compound of the present invention or a pharmaceutically acceptable salt thereof may be administered as is or in a pharmaceutically acceptable non-toxic and inert carrier, for example, It is administered to mammals including humans as a pharmaceutical composition containing 0.001% to 99.5%, preferably 0.1% to 90%.
  • the pharmaceutical composition according to the invention is preferably administered in dosage unit form.
  • the pharmaceutical composition can be administered intratissue, orally, intravenously, locally (transdermally, ophthalmically, etc.), or rectally. Of course, it is administered in a dosage form suitable for these administration methods.
  • the appropriate amount of the active ingredient in the salt is 0.1 mg to 5 g/adult, preferably 1 mg to 500 mg/adult per day. In some cases, a lower dose than this may be sufficient, and in other cases, a higher dose may be required. Usually, it can be administered once a day or in several divided doses, or it can be administered continuously intravenously over 1 to 24 hours.
  • the compound of the present invention or a pharmaceutically acceptable salt thereof is used in the range of 200 mg to 600 mg per day, preferably in the range of 100 mg to 300 mg twice a day, for oral administration. It can also be used at 300 mg twice a day.
  • Test Example 1 Effect on reducing visceral volume in patients with myelofibrosis Within 14 days before the start of administration of Compound A, the platelet count and baseline spleen of patients with myelofibrosis were measured. Compound A was orally administered daily for one cycle of 28 days. Compound A was taken by patients at least 2 hours after a meal and at least 1 hour before the next meal. The starting dose cohort (first cohort) was 300 mg per day. The appropriate number of 100 mg tablets were supplied to the patient and taken by the patient at the specified dose level.
  • spleen size was measured using magnetic resonance imaging (MRI), and spleen volume was calculated (CT was used for patients who could not use MRI).
  • CT magnetic resonance imaging
  • Spleen volume reduction rate (spleen volume 24 weeks after the start of administration - spleen volume before the start of administration) / spleen volume before the start of administration x 100
  • Compound A was useful in treating high-risk patients.
  • Compound A is orally administered daily for one cycle of 28 days.
  • Compound A is taken by the patient at 12 hour intervals, at least 2 hours after a meal and at least 1 hour before the next meal.
  • the appropriate number of 100 mg tablets are supplied to the patient and 300 mg (3 tablets) are taken by the patient twice a day (total daily dose of 600 mg).
  • Formulation example 1 Tablets (oral tablets) 5.0 mg of the compound of the present invention in Example 1 in 80 mg of 1 tablet of prescription Corn starch 46.6mg Crystalline cellulose 24.0mg Methylcellulose 4.0mg Magnesium stearate 0.4mg The mixed powder in this proportion is compressed into tablets by a conventional method to form oral tablets.
  • Formulation example 2 Tablets (oral tablets) 5.0 mg of the compound of the present invention in Example 2 in 80 mg of 1 tablet of prescription Corn starch 46.6mg Crystalline cellulose 24.0mg Methylcellulose 4.0mg Magnesium stearate 0.4mg The mixed powder in this proportion is compressed into tablets by a conventional method to form oral tablets.
  • a pharmaceutical composition containing the compound of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient can be used as a therapeutic agent for high-risk myelofibrosis.

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Abstract

La présente invention concerne un nouvel agent thérapeutique pour la myélofibrose à haut risque, ledit agent contenant un composé représenté par la formule générale [1] (dans la formule, R1, R2, R3, R4, R5 et X sont tels que définis dans la description) ou un sel pharmaceutiquement acceptable de celui-ci en tant que principe actif.
PCT/JP2022/012705 2022-03-18 2022-03-18 Agent thérapeutique pour myélofibrose à haut risque WO2023175932A1 (fr)

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PCT/JP2022/012705 WO2023175932A1 (fr) 2022-03-18 2022-03-18 Agent thérapeutique pour myélofibrose à haut risque
PCT/JP2023/010686 WO2023176972A1 (fr) 2022-03-18 2023-03-17 Agent thérapeutique pour myélofibrose à haut risque

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PCT/JP2023/010686 WO2023176972A1 (fr) 2022-03-18 2023-03-17 Agent thérapeutique pour myélofibrose à haut risque

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010090290A1 (fr) * 2009-02-06 2010-08-12 日本新薬株式会社 Dérivé d'aminopyrazine et médicament correspondant

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010090290A1 (fr) * 2009-02-06 2010-08-12 日本新薬株式会社 Dérivé d'aminopyrazine et médicament correspondant

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
ANONYMOUS: "NS-018", MEDKOO BIOSCIENCES, 1 January 2017 (2017-01-01), pages 1 - 2, XP093092776, Retrieved from the Internet <URL:https://www.medkoo.com/products/5685> [retrieved on 20231018] *
VERSTOVSEK S, TALPAZ M, RITCHIE E, WADLEIGH M, ODENIKE O, JAMIESON C, STEIN B, UNO T, MESA R A: "A phase I, open-label, dose-escalation, multicenter study of the JAK2 inhibitor NS-018 in patients with myelofibrosis", LEUKEMIA, NATURE PUBLISHING GROUP UK, LONDON, vol. 31, no. 2, 1 February 2017 (2017-02-01), London, pages 393 - 402, XP093092316, ISSN: 0887-6924, DOI: 10.1038/leu.2016.215 *

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