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WO2019245010A1 - Agent thérapeutique contre une fibrose kystique - Google Patents

Agent thérapeutique contre une fibrose kystique Download PDF

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Publication number
WO2019245010A1
WO2019245010A1 PCT/JP2019/024614 JP2019024614W WO2019245010A1 WO 2019245010 A1 WO2019245010 A1 WO 2019245010A1 JP 2019024614 W JP2019024614 W JP 2019024614W WO 2019245010 A1 WO2019245010 A1 WO 2019245010A1
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group
cftr
cftr function
independently selected
salt
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Japanese (ja)
Inventor
聡 宗岡
嘉晃 冨森
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Daiichi Sankyo Co Ltd
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Daiichi Sankyo Co Ltd
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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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/443—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with oxygen as a ring hetero atom
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • 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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention has a G protein-coupled receptor 39 (G protein-coupled receptor 39, which may be abbreviated as GPR39 in the present specification) agonistic action, and activates a calcium-dependent chloride channel (GPR39) through activation of GPR39.
  • G protein-coupled receptor 39 which may be abbreviated as GPR39 in the present specification
  • CaCC calcium-dependent chloride channel
  • CFTR Regulator
  • Cystic fibrosis is a serious hereditary disease caused by a genetic mutation in CFTR, a type of chloride channel, and it is estimated that there are more than 70,000 patients worldwide. In recent years, although treatments have been developed, the average life expectancy is about 40 years, so that a satisfactory treatment has not yet been established.
  • CFTR is a major cAMP-dependent anion channel expressed on the luminal membrane of whole epithelial cells.
  • the function of this channel is reduced by gene mutation, the transport of ions and water through the epithelium / mucosa is impaired in the respiratory tract, intestinal tract, pancreatic duct, bile duct, sweat duct, etc., resulting in excessive mucus / secretion in the lumen.
  • CFTR was identified as a causative gene for cystic fibrosis, studies on cystic fibrosis have progressed, and it has been reported that about 1900 or more mutations exist at present. Of these mutations, they are classified into six classes according to the CFTR dysfunction caused by the mutations (class I; nonsense mutation, class II; protein misfolding mutation, class III; mutation in abnormal channel opening, class IV; channel conductance). Mutations, class V; mutations that decrease the amount of CFTR produced, class VI; mutations that decrease the stability of CFTR), and particularly the class I, class II, and class III mutations, since the chloride ion is hardly secreted, and the symptoms are severe. The unmet medical needs are very high.
  • VX-770 and Lumacaftor may be referred to as VX-809.
  • Kalydeco is a class III and class IV mutation in some patients
  • Orkambi is a class II.
  • Symdeko has an effect on the ⁇ F508 homozygous mutation and only on some patients with the ⁇ F508 homozygous mutation or the class III and class IV mutations.
  • Orkambi and Symdeko were confirmed to have a statistically significant respiratory function-improving effect, but their efficacy was limited, and there were many patients who did not yet have a sufficient therapeutic drug, centering on the class I and class II mutations. .
  • One of the methods for solving these problems is to open a chloride channel other than CFTR to substitute for a malfunction of CFTR. If a compound having such a profile can be obtained, it is considered that all cystic fibrosis patients can be treated theoretically without depending on the mutation of CFTR.
  • they open chloride channels other than CFTR they can be used in combination with existing CFTR agents such as Kalydeco (registered trademark), Orkambi (registered trademark), and Symdeko (registered trademark) to further enhance the efficacy of the drug. There is expected.
  • Denufosol which is a P2Y 2 (a type of G protein-coupled receptor (GPCR)) agonist
  • GPCR G protein-coupled receptor
  • CaCC Calcium-activated Chloride Channel
  • a low-molecular compound that directly acts on CaCC and activates it has been screened and reported to be promising as a therapeutic agent for cystic fibrosis (Non-Patent Document 2). It is unknown.
  • the preceding therapeutic drug for cystic fibrosis is only effective for patients with limited mutations, and the drug efficacy against Orkambi or Symdeko's ⁇ F508 homozygous mutation is not sufficient. Is eagerly awaited. Although there has been a therapeutic concept of opening a chloride channel other than CFTR and substituting a CFTR dysfunction, a compound showing a medicinal effect in clinical practice has not been obtained at present.
  • In-vitro drug efficacy evaluation is based on the point that a three-dimensional culture system using airway epithelial cells derived from a cystic fibrosis patient (Air-Liquid Interface Interfacial Assay; ALI assay) absorbs water quickly and hardly secretes water. Since it is close to the lung condition of cystic fibrosis patients, it is widely used as a drug efficacy evaluation system. In fact, Kalydeco moved water in the ALI assay (Non-patent Document 3), and was developed as a therapeutic agent for cystic fibrosis, and its clinical efficacy was confirmed (Non-patent Document 4).
  • GPR39 G protein-coupled receptor 39
  • the ligand for GPR39 has been unknown for a long time, but since it is a member of the ghrelin receptor family, the ligand was presumed to be a peptide, and there were times when obestatin was considered to be a natural ligand.
  • obestatin is not a GPR39 ligand, but zinc (Zn 2+ ) is said to be a GPR39 ligand.
  • GPR39 is expressed in mouse @ intestinal @ fibroblast-like @ cells, and it has been reported that GPR39 activation is associated with CaCC activation (Non-Patent Document 5), but cells derived from cystic fibrosis patients have been reported. Is unknown, and there is no report that a compound capable of activating GPR39 and continuously opening CaCC has been obtained.
  • Non-Patent Document 6 AZ7914, AZ4237, AZ1395
  • Non-Patent Document 7 pyridylpyrimidine compound
  • the present inventors have found that, in cystic fibrosis caused by CFTR mutation, if a chloride channel different from CFTR that causes the disease can be opened, the dysfunction of CFTR can be substituted, leading to treatment.
  • a pyrimidine derivative having a specific chemical structure opens CaCC via GPR39 agonism and is effective in treating cystic fibrosis independently of CFTR.
  • the pyrimidine derivative when the pyrimidine derivative is administered in combination with a CFTR function improving agent or an ENaC inhibitor, the pyrimidine derivative exerts an excellent effect on the treatment of cystic fibrosis, thereby completing the present invention.
  • the medicament according to [1] or [2] wherein the medicament is contained as active ingredients of different preparations, and is administered at the same time or at different times.
  • [4] (a) a compound represented by the formula (I) or a pharmaceutically acceptable salt thereof and (b) at least one drug independently selected from the group consisting of a CFTR function improving agent and an ENaC inhibitor; The medicament according to [1] or [2], which is contained in a single preparation.
  • [5] (a) a compound represented by the formula (I) or a pharmaceutically acceptable salt thereof and (b) at least one drug independently selected from the group consisting of a CFTR function improving agent and an ENaC inhibitor
  • [6] The method according to any one of [1] to [5], which is for a patient who has been treated with at least one drug independently selected from the group consisting of a CFTR function improving drug and an ENaC inhibitor. Medicine.
  • At least one drug independently selected from the group consisting of a CFTR function improving agent and an ENaC inhibitor is a CFTR function improving agent, wherein the CFTR function improving agent is CFTR potentiator, CFTR collector, or CFTR amplifier.
  • At least one drug independently selected from the group consisting of a CFTR function improver and an ENaC inhibitor is a CFTR function improver, and the CFTR function improver is a group consisting of CFTR potentiator and CFTR collector
  • At least one drug independently selected from the group consisting of a CFTR function improving agent and an ENaC inhibitor is a CFTR function improving agent, wherein the CFTR function improving agent is Ivacaftor, QBW251, VX-561.
  • the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof is bis [5- (2-chlorobenzyl) -4-methoxy-6-methylpyrimidine-2-carboxylic acid] magnesium salt.
  • the medicament according to any one of [1] to [11].
  • At least one drug independently selected from the group consisting of a CFTR function improving agent and an ENaC inhibitor is a CFTR function improving agent, wherein the CFTR function improving agent is a group consisting of CFTR potentiator and CFTR collector.
  • At least one drug independently selected from the group consisting of CFTR function improvers and ENaC inhibitors is a CFTR function improver, wherein the CFTR function improver is Ivacaftor, QBW251, VX-561.
  • At least one drug independently selected from the group consisting of CFTR function improving agents and ENaC inhibitors is an ENaC inhibitor, and the ENaC inhibitor is selected from the group consisting of QBW276, SPX-101 and AZD5634.
  • the pharmaceutically acceptable salt thereof according to any one of [14] to [16].
  • the pharmaceutically acceptable salt is a magnesium salt, a calcium salt, a zinc salt, a sodium salt, a tert-butylamine salt or a diisopropylamine salt.
  • the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof is magnesium bis [5- (2-chlorobenzyl) -4-methoxy-6-methylpyrimidine-2-carboxylic acid].
  • a pharmaceutically acceptable salt thereof and (b) at least one drug independently selected from the group consisting of CFTR function improving agents and ENaC inhibitors How to treat the disease.
  • At least one drug independently selected from the group consisting of (a) the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof, and (b) a CFTR function improving agent and an ENaC inhibitor The therapeutic method according to [24] or [25], which is a kit preparation containing them.
  • At least one drug independently selected from the group consisting of a CFTR function improving agent and an ENaC inhibitor is a CFTR function improving agent, wherein the CFTR function improving agent is a group consisting of CFTR potentiator and CFTR collector.
  • At least one drug independently selected from the group consisting of CFTR function improvers and ENaC inhibitors is a CFTR function improver, wherein the CFTR function improver is Ivacaftor, QBW251, VX-561.
  • the pharmaceutically acceptable salt is a magnesium salt, a calcium salt, a zinc salt, a sodium salt, a tert-butylamine salt or a diisopropylamine salt. .
  • the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof is bis [5- (2-chlorobenzyl) -4-methoxy-6-methylpyrimidine-2-carboxylic acid] magnesium salt
  • (a) a compound represented by the formula (I) or a pharmaceutically acceptable salt thereof, and (b) at least one drug independently selected from the group consisting of a CFTR function improving agent and an ENaC inhibitor The therapeutic method according to any one of [24] to [36], wherein the administered subject is a warm-blooded animal.
  • a pharmaceutically acceptable salt refers to a salt that has no significant toxicity and can be used as a medicament. Since the compound represented by the formula (I) of the present invention has an acidic group, it can be converted to a salt by reacting with a base.
  • Such salts include, for example, alkali metal salts such as sodium salt, potassium salt and lithium salt, alkaline earth metal salts such as calcium salt and magnesium salt, metal salts such as aluminum salt, iron salt and zinc salt.
  • Inorganic salts such as ammonium salts, tert-butylamine salts, tert-octylamine salts, diisopropylamine salts, dibenzylamine salts, morpholine salts, glucosamine salts, phenylglycine alkyl ester salts, ethylenediamine salts, N-methylglucamine salts Guanidine salt, diethylamine salt, triethylamine salt, dicyclohexylamine salt, N, N'-dibenzylethylenediamine salt, chloroprocaine salt, procaine salt, diethanolamine salt, N-benzylphenethylamine salt, piperazine salt, tetramethylammonium And organic amine salts such as
  • Examples of preferred salts include magnesium salt, calcium salt, zinc salt, sodium salt, tert-butylamine salt and diisopropylamine salt.
  • hydrochloride includes salts that can be formed, such as monohydrochloride, dihydrochloride, trihydrochloride
  • magnesium salt includes salts that can be formed, such as monomagnesium, ⁇ ⁇ ⁇ ⁇ ⁇ magnesium.
  • “monoacid salt” and “monobasic salt” may be abbreviated as “acid salt” in which "one” is omitted.
  • “Hydrochloride” and “monomagnesium salt” may be indicated as “magnesium salt”.
  • the compound represented by the formula (I) of the present invention or a pharmaceutically acceptable salt thereof may be left in the atmosphere or recrystallized to absorb adsorbed water or take in water molecules.
  • hydrates, and such hydrates are also included in the compounds of the present invention or pharmaceutically acceptable salts.
  • the compound of the present invention represented by the formula (I) or a pharmaceutically acceptable salt thereof absorbs a certain solvent by being left in a solvent or recrystallized in the solvent, It may be possible to form a solvate, and such a solvate is also included in the compound of the present invention or a pharmaceutically acceptable salt.
  • the solvent capable of forming a solvate is not particularly limited as long as it does not have remarkable toxicity and can be used as a medicine.
  • ethanol 1-propanol, 2-propanol, 1-butanol, 2-butanol, Butanol, acetone, methyl ethyl ketone, methyl isobutyl ketone, dimethyl sulfoxide, ethyl formate, ethyl acetate, propyl acetate, diethyl ether, tetrahydrofuran, formic acid, acetic acid, pentane, heptane, cumene, anisole and the like.
  • each of the hydrates or solvates formed by combining the compound represented by the formula (I) of the present invention or a pharmaceutically acceptable salt thereof with water or a solvent in any ratio, or a mixture thereof Included in the invention.
  • hydrates that can be formed such as monohydrate, dihydrate, hemihydrate, 3/2 hydrate, and solvates, disolvates, and 1/2 solvents
  • Solvates that can be formed such as solvates, 3/2 solvates, are encompassed by the present invention.
  • ⁇ hydrate '' or ⁇ solvate '' is described without specifying the hydration number or solvation number, any number of hydrates or solvates is included. It is.
  • More specific preferred examples of the compound represented by the formula (I) of the present invention or a pharmaceutically acceptable salt thereof include 5- (2-chlorobenzyl) -4-methoxy-6-methylpyrimidine-2- Examples include carboxylic acid or its magnesium salt, calcium salt, zinc salt, sodium salt, tert-butylamine salt or diisopropylamine salt. These may be in the form of hydrates.
  • More specific one embodiment of the compound of the present invention includes 5- (2-chlorobenzyl) -4-methoxy-6-methylpyrimidine-2-carboxylic acid hydrate, magnesium salt hydrate, calcium salt hydrate, Zinc salt hydrate, sodium salt anhydride, tert-butylamine salt anhydride or diisopropylamine salt anhydride, more preferably hydrate or magnesium salt hydrate.
  • a CFTR function improving drug is a drug that directly acts on CFTR dysfunction caused by mutation of CFTR that is a causative gene of cystic fibrosis and improves the function thereof.
  • CFTR function improving drugs include CFTR @ potentiator, CFTR @ corrector, CFTR @ amplifier, RNA therapy and Gene therapy.
  • CFTR ⁇ potentiators act on and open CFTR with class III and class IV mutations, thereby improving its function.
  • Representative examples include Ivacaftor (VX-770); QBW251 (Am ⁇ J ⁇ Respir ⁇ Crit ⁇ Care ⁇ Med .; 193: A7789 (2016)); VX-561 (J ⁇ Pharmacol ⁇ Exp ⁇ Ther .; 362: 359-67 (2017)); PTI-808 (Cystic Fibrosis Foundation 2017 ANNUAL REPORT); GLPG1837 (J Med Chem .; 61: 1425-1435 (2016)); GLPG2451 or GLPG 3067 (J Cyst Fibros.); Compounds described in International Publication WO2015 / 018823; compounds described in International Publication WO2018 / 073175.
  • CFFurthermore CFTR corrector normalizes the dysfunction by expressing CFTR having class II mutation on the cell surface.
  • Representative examples include Lumacaftor (VX-809); Tezacaftor; VX-445, VX-440, VX-152 or VX-659 (J ⁇ Cyst ⁇ Fibros .; 17 (S2): S52-60 (2016)); FDL169 ( 27 (2016)); GLPG2222 (J Med Chem .; 61: 1436-1449 (2016)); GLPG2851 or GLPG2737 (JCyst Fibros .; 17 (S2): S52-60 (2018)); Compounds described in International Publication WO2015 / 018823; Compounds described in International Publication WO2018 / 073175; PTI-801 (J Cyst Fibros .; 17 (S2): S52-60 (2018), Cystic ⁇ ibrosis Foundation 2017 ANNUAL REPORT) and the like.
  • CFCFTR amplifier normalizes dysfunction by enhancing the expression of CFTR protein.
  • Representative examples include PTI-428 (J @ Cyst Fibros .; 17 (S3): S1-2 (2016), J @ Transl @ Med .; 15:84 (2017), Cystic @ Fibrosis ⁇ Foundation 2017 2017 ANNUAL REPORT, N- [trans. -3- [5-[(1R) -1-hydroxyethyl] -1,3,4-oxadiazol-2-yl] cyclobutyl] -3-phenyl-1,2-oxazole-5-carboxamide, International Publication WO2016 / 105485, and the like.
  • RNARNA therapy also restores the expression of mRNA encoding CFTR and normalizes its dysfunction by enhancing the expression of CFTR protein.
  • Representative examples include Eluforsen (QR-010, J Transl Med .; 15:84 (2017), Cyclic Fibrosis Foundation 2017 ANNUAL REPORT), the antisense oligonucleotide described in International Publication WO2014 / 011053, MRT5005FyCy 17 (S3): S16 (2016), Cyclic Fibrosis Fundation 2017 2017 ANNUAL REPORT, and the like.
  • Gene therapy functions by introducing a gene encoding CFTR using a virus or a non-viral vector, or by repairing an abnormality of the gene encoding CFTR by a genome editing technique such as CRISPR / Cas9. Normalize the abnormalities (Front Pharmacol .; 9: 396 (2016), J @ Transl Med .; 15:84 (2017)).
  • particularly preferred examples of the CFTR function improving agent are at least one kind independently selected from the group consisting of CFTR @ potentiator and CFTR @ corrector.
  • a preferred specific example is at least one independently selected from the group consisting of Ivacaftor, Lumacaftor and Tezacaftor.
  • two or more CFTR function-improving agents may be used in combination.
  • Orkambi registered trademark
  • Symdeko registered trademark
  • Tezacaftor and Ivacaftor VX -445 and Tezacaftor and Ivacaftor the mixture
  • Cystic Fibrosis Foundation 2017 ANNUAL REPORT mixture of VX-440 and Tezacaftor and Ivacaftor, VX-152 and Tezacaftor and Ivacaftor the mixture, VX-659 and Tezacaftor and Ivacaftor the mixture
  • J Cyst Fibros .; 17 (S3): S3 (2016) Cystic Fibrosis ⁇ compound, described in International Publication No.
  • WO2017 / 060880 a combination of GLPG2451, GLPG2222 and GLPG2737, a combination of PTI-428, PTI-801 and PTI-808 (Expert Rev. MediGed.Dev. 3: 107-117 (2016)) is also preferably used.
  • the ENaC inhibitor inhibits the opening of ENaC (epithelial sodium channel) expressed on the surface of epithelial cells, or inhibits the absorption of sodium ions by internalizing ENaC expressed on the surface of epithelial cells.
  • ENaC epihelial sodium channel
  • It is a drug.
  • Representative examples include QBW276 (Cystic Fibrosis Foundation 2017 ANNUAL REPORT), Bioorg Med Chem Chem Lett. 22 (2): 929-932 (2012); Bioorg ⁇ Chem ⁇ Lett.
  • CFTR function improving drugs and ENaC inhibitors can be used in combination with one or more drugs.
  • the compound of the present invention represented by the formula (I) or a pharmaceutically acceptable salt thereof has a strong chloride ion secretion action through GPR39 agonist action and transfers water. Since this compound can open a chloride channel different from CFTR which causes disease, it exhibits an excellent therapeutic effect when combined with a CFTR function improving agent or an ENaC inhibitor. Therefore, the medicament / therapeutic method for treating cystic fibrosis by the combination of the compound of the present invention or a pharmaceutically acceptable salt thereof and a CFTR function-improving agent can be performed from class I to VI regardless of the type of CFTR mutation. The therapeutic effect can be exhibited in any of the above.
  • a preferred treatment target is a patient with a class II ⁇ F50850homozygous mutation, a class III mutation, and a class IV mutation in which an existing CFTR improving drug is used.
  • FIG. 1 is a graph showing changes in the expression level of human GPR39 (mRNA expression analysis) in CuFi-1 cells, a bronchial epithelial cell line derived from a cystic fibrosis patient, by siRNA treatment.
  • FIG. 2 is a graph showing the influence of each compound on chloride secretion activity by treatment with siRNA in CuFi-1 cells. The vertical axis represents the rate of increase when comparing the average value of the five fluorescence values from 110 to 120 seconds during the measurement for 120 seconds with the average value of the fluorescence values at 17 points from 1 to 34 seconds. ing.
  • FIG. 3 is a graph showing the water transfer effect of each compound in MucilAir-CF TM cells (lot number MD048502) having ⁇ F508 homozygous, which is a Class II mutation of CFTR.
  • the vertical axis indicates the moisture remaining ratio in the upper layer.
  • N 3-20 means and standard deviation.
  • Dunnett's multiple comparison test was performed with the group to which no compound was added, and the group having a p value of 0.01 or less is indicated by **. # Indicates that the p-value by the Student's t-test was 0.032 for the group without the compound and the group with the combination of VX-809 (30 ⁇ M) / VX-770 (1 ⁇ M).
  • FIG. 3 is a graph showing the water transfer effect of each compound in MucilAir-CF TM cells (lot number MD048502) having ⁇ F508 homozygous, which is a Class II mutation of CFTR.
  • the vertical axis indicates the moisture remaining ratio in the upper layer.
  • FIG. 4 is a graph showing the water transfer effect of each compound in MucilAir-CF TM cells (lot number MD020802) having 2184 ⁇ A + W1282X, which is a Class I mutation of CFTR.
  • Dunnett's multiple comparison test was performed with the group to which no compound was added, and the group having a p value of 0.01 or less is indicated by **. ## indicates that the p-value by the Student's t-test was 0.0017 for the group of Example 1 (100 ⁇ M) and the group of VX-809 (30 ⁇ M) / VX-770 (1 ⁇ M). It indicates that there is.
  • FIG. 5 is a graph showing the water transfer effect of each compound in MucilAir-CF TM cells (Lot No. MD062011) having N1303K heterozygous, which is a Class II mutation of CFTR.
  • Dunnett's multiple comparison test was performed with the group to which no compound was added, and the group having a p value of 0.01 or less is indicated by **.
  • FIG. 6 shows a mixture of VX-809 (30 ⁇ M) / VX-770 (1 ⁇ M) alone and the compound of Example 1 in MucilAir-CF TM cells (lot No.
  • MD048502 having ⁇ F508 homozygous which is a Class II mutation of CFTR.
  • Dunnett's multiple comparison test was performed with the combination of VX-809 (30 ⁇ M) / VX-770 (1 ⁇ M) and the group with a p-value of 0.01 or less is indicated by **. # Indicates that the p-value by the Student's t-test was 0.032 for the group without the compound and the group with the combination of VX-809 (30 ⁇ M) / VX-770 (1 ⁇ M).
  • the compound of the present invention can be produced by various production methods, and the production methods shown below are examples, and the present invention should not be construed as being limited thereto.
  • the compound represented by the formula (I) and a production intermediate thereof can be produced using various known reactions described below.
  • the functional group may be protected with a suitable protecting group at the stage of the raw material or the intermediate. Examples of such a functional group include a hydroxyl group, a carboxy group, an amino group, and the like.
  • the kind of the protecting group and the conditions for introducing and removing the protecting group are, for example, Protective Groups, Organic, Synthesis, Third Edition. (TW Green @ and PGM Wuts, John Wiley & Sons, Inc., New York) can be referred to.
  • the compound represented by the formula (I) (represented as compound 1a in the following reaction formula) can be produced, for example, by the following reaction formula.
  • G is a 2-chlorophenyl group
  • R 1 is a methyl group
  • Q 1 is represents a methylene group
  • P a, P b, P c represents a protecting group
  • R 2a is a methoxy group.
  • Conversion of Compound 2a to Compound 3a can be performed by using a suitable solvent that does not adversely affect the reaction (eg, benzene, toluene, diethyl ether, dichloromethane, tetrahydrofuran, or N, N-dimethylformamide). Or a mixed solvent thereof) in a suitable base (eg, sodium hydride, sodium methoxide, potassium tert-butoxide, etc.) at ⁇ 30 ° C. to the boiling point of the solvent used in the reaction, preferably at 0 ° C. to 100 ° C. (A mixture thereof) in the presence of the ester compound 2a and the corresponding alkyl halide.
  • the reaction time is preferably from 10 minutes to 72 hours, more preferably from 8 hours to 24 hours.
  • Compound 2a which is a raw material for production can be synthesized according to a commercially available or known method.
  • (2) Conversion of Compound 3a to Compound 5a Conversion of Compound 3a to Compound 5a is performed using a suitable solvent that does not adversely influence the reaction (eg, N, N-dimethylformamide, acetone, or the like, or a mixed solvent thereof).
  • a suitable base eg, triethylamine, N, N-diisopropylethylamine, 4-dimethylaminopyridine, N-methylmorpholine, pyridine, 2,6- Compound 4 in the presence of lutidine, diazabicyclo [5.4.0] undec-7-ene, or the like, or a mixture thereof.
  • An excess amount can be used as the amount of the base.
  • the reaction time is preferably 1 hour to 72 hours, more preferably 8 hours to 24 hours.
  • Compound 4 as a raw material for production can be synthesized according to the method described in Reference Example.
  • (3) Conversion of Compound 5a to Compound 6a Conversion of Compound 5a to Compound 6a can be performed by using a suitable solvent that does not adversely affect the reaction (eg, toluene, 1,4-dioxane, 1,2-dichloroethane, tetrahydrofuran, or the like, or In a mixed solvent thereof), a chlorinating agent such as carbon tetrachloride, trichloroacetonitrile, or N-chlorosuccinimide is used in the presence of triphenylphosphine at ⁇ 30 ° C.
  • a suitable solvent that does not adversely affect the reaction eg, toluene, 1,4-dioxane, 1,2-dichloroethane, tetrahydrofuran, or the like, or In a mixed solvent thereof
  • a chlorinating agent such as
  • the reaction can be carried out.
  • the reaction time is preferably from 10 minutes to 12 hours, more preferably from 30 minutes to 2 hours.
  • Pb is a methyl group
  • the compound is dissolved in a suitable solvent (for example, chloroform, dichloromethane, tetrahydrofuran, 1,4-dioxane or the like, or a mixed solvent thereof) which does not adversely affect the reaction, at a temperature of -30 ° C to 100 ° C.
  • the reaction can be carried out by treating a suitable chlorinating agent (eg, oxalyl chloride, thionyl chloride, phosphorus oxychloride, etc.) at a temperature up to the boiling point of the solvent used in the reaction, preferably from room temperature to 100 ° C.
  • a suitable chlorinating agent eg, oxalyl chloride, thionyl chloride, phosphorus oxychloride, etc.
  • the reaction time is preferably from 10 minutes to 24 hours, more preferably from 30 minutes to 12 hours.
  • a base such as triethylamine, N, N-dimethylaniline, N, N-diethylaniline can be added. Further, N, N-dimethylformamide or the like can be added as a reaction accelerator.
  • the reaction conditions for deprotection varies depending on the type of P b.
  • Pb is a methyl group
  • it is added in a suitable solvent that does not adversely influence the reaction (eg, dichloromethane, chloroform, etc., or a mixed solvent thereof) from ⁇ 78 ° C. to the boiling point of the solvent used in the reaction, preferably ⁇ 40.
  • a deprotecting agent such as boron tribromide at a temperature from °C to room temperature.
  • the reaction time is preferably from 1 hour to 72 hours, more preferably from 2 hours to 24 hours.
  • the reaction can be carried out by treating with trifluoroacetic acid, hydrochloric acid, formic acid or the like at -30 ° C to the boiling point of the solvent used in the reaction, preferably at -20 ° C to room temperature.
  • the reaction time is preferably from 10 minutes to 72 hours, more preferably from 30 minutes to 24 hours.
  • Conversion of Compound 7a to Compound 8a Conversion of Compound 7a to Compound 8a can be carried out by a general oxidation reaction for converting a primary alcohol to a carboxylic acid.
  • Typical oxidizing agents include potassium permanganate, chromium trioxide and dilute sulfuric acid (Jones oxidation), or (2,2,6,6-tetramethyl-1-piperidinyl) oxyl (TEMPO) and a co-oxidizing agent ( Hypochlorite, bromite, N-chlorosuccinimide, etc.).
  • the solvent used in the reaction include acetone, acetonitrile, water and the like, or a mixed solvent thereof.
  • the reaction temperature is from ⁇ 78 ° C. to 100 ° C. or the boiling point of the solvent, preferably from room temperature to 80 ° C.
  • the time can be from 1 hour to 48 hours, preferably from 1 hour to 24 hours.
  • the aldehyde compound obtained by oxidizing the compound 7a can be oxidized again to obtain the compound 8a.
  • the oxidation reaction for obtaining an aldehyde compound include chromic acid [pyridinium chlorochromate (PCC), pyridinium dichromate (PDC), etc.], dimethylsulfoxide and oxalyl chloride (Swern oxidation), dimethylsulfoxide and acetic anhydride, dimethylsulfoxide and trioxide.
  • PCC pyridinium chlorochromate
  • PDC pyridinium dichromate
  • Swern oxidation dimethylsulfoxide and oxalyl chloride
  • dimethylsulfoxide and acetic anhydride dimethylsulfoxide and trioxide.
  • Conversion from Compound 8a to Compound 9a can be carried out by a general carboxy group protection reaction.
  • a suitable acid catalyst eg, hydrogen chloride, sulfuric acid, or thionyl chloride
  • the reaction time is preferably from 10 minutes to 72 hours, more preferably from 30 minutes to 24 hours.
  • a suitable esterifying agent for example, from room temperature to the boiling point of the solvent used in the reaction, preferably from room temperature to 100 ° C.
  • a tert-butyl ester can be obtained by treating N, N-dimethylformamide di-tert-butyl acetal, O-tert-butyl-N, N′-diisopropylisourea, or the like.
  • the reaction time is preferably from 10 minutes to 72 hours, more preferably from 30 minutes to 24 hours.
  • Conversion of Compound 9a to Compound 10a is performed by a nucleophilic substitution reaction of Compound 9a with an alcohol, amine, or thiol.
  • a nucleophilic substitution reaction of Compound 9a with an alcohol, amine, or thiol.
  • the substitution reaction is performed in an appropriate solvent (tetrahydrofuran, acetone, acetonitrile, 1,4-dioxane, dimethyl sulfoxide, or the like, or a mixed solvent thereof) that does not adversely affect the reaction.
  • the reaction can be carried out by treating an appropriate base (eg, sodium hydride, potassium carbonate, cesium carbonate, etc.) at a temperature from room temperature to the boiling point of the solvent used in the reaction, preferably from room temperature to 100 ° C.
  • the reaction time is preferably from 6 hours to 72 hours, more preferably from 12 hours to 24 hours.
  • the amount of the base to be used may be 1 to excess molar equivalent relative to compound 9a, and more preferably 1 to 5 molar equivalents.
  • the amount of the alcohol to be used may be 1 to an excess molar equivalent based on compound 10a, and the reaction may be carried out using alcohol as a solvent. It is also possible to carry out the reaction using a metal alkoxide. Further, a catalytic amount of crown ether may be added.
  • the solvent used in the reaction may be heated from room temperature in a suitable solvent (tetrahydrofuran, 1,4-dioxane, or the like, or a mixed solvent thereof) which does not adversely influence the reaction.
  • a suitable solvent tetrahydrofuran, 1,4-dioxane, or the like, or a mixed solvent thereof
  • a suitable base eg, an inorganic base such as potassium carbonate or cesium carbonate, an organic base such as triethylamine, N, N-diisopropylethylamine
  • the reaction time is preferably from 6 hours to 72 hours, more preferably from 12 hours to 24 hours.
  • the amount of the base to be used may be 1 to excess molar equivalent relative to compound 9a, and more preferably 1 to 2 molar equivalents.
  • the use amount of the amine may be 1 to 2 molar equivalents when a base is used, and preferably 2 to 30 molar equivalents to compound 9a when a base is not used.
  • the above reaction can also be performed by treating in a sealed tube or under microwave irradiation.
  • the reaction time is preferably from 10 minutes to 72 hours, more preferably from 30 minutes to 24 hours.
  • P c is a tert-butyl group
  • it is treated with trifluoroacetic acid, hydrochloric acid, formic acid or the like at ⁇ 30 ° C. to the boiling point of the solvent used in the reaction, preferably at ⁇ 20 ° C. to room temperature, in addition to the above deprotection reaction. This can also be implemented.
  • the reaction time is preferably from 10 minutes to 72 hours, more preferably from 30 minutes to 24 hours.
  • Conversion of compound 8a to compound 1a can be carried out by the same substitution reaction as described in the above-mentioned [Production method 1] (7).
  • the compound represented by the formula (I) (represented as compound 1c in the following reaction formula) can be produced, for example, by the following reaction formula using 6c that can be produced by the above [Production method 1] as a starting material.
  • G, R 1 and P b have the same meaning as described above, but P b is preferably a tert-butyl group.
  • Q 2 represents a methylene group.
  • M 1c represents a methyl group.
  • Conversion of Compound 6c to Compound 11c The conversion of Compound 6c to Compound 11c can be carried out by the same substitution reaction as in the case of using the alcohol described in (7) of [Production Method 1].
  • Conversion of Compound 11c to Compound 12c Conversion of Compound 11c to Compound 12c can be carried out by the same general deprotection reaction as described in the above-mentioned [Production Method 1] (4).
  • Conversion of compound 12c to compound 1c Conversion of compound 12c to compound 1c can be carried out by the same general oxidation reaction as described in the above-mentioned [Production method 1] (5).
  • the “medicament characterized by being administered in combination (preferably, a medicament for treating cystic fibrosis) / therapeutic method (preferably, a method for treating cystic fibrosis)” includes the formula (a) Or a pharmaceutically acceptable salt thereof, and (b) at least one drug selected from the group consisting of CFTR function improving agents and ENaC inhibitors, preferably for the treatment of cystic fibrosis.
  • At least one drug selected from the group consisting of (a) a compound represented by the formula (I) or a pharmaceutically acceptable salt thereof, and (b) a CFTR function-improving agent and an ENaC inhibitor is used.
  • administered in combination means that, during a certain period of time, the administered subject is (a) a compound represented by the formula (I) or a pharmaceutically acceptable salt thereof, (b) a CFTR function improving agent and It means that at least one drug selected from the group consisting of ENaC inhibitors is taken into the body.
  • the included formulations may be administered, or each may be separately formulated and administered separately. When formulated separately, the timing of administration is not particularly limited, and they may be administered simultaneously, or may be administered at different times at different times or on different days.
  • each preparation is administered according to each administration method, so that the administration may be the same or different.
  • the administration method (administration route) of each formulation may be the same or may be administered by different administration methods (administration routes).
  • (a) a compound represented by the formula (I) or a pharmaceutically acceptable salt thereof and (b) at least one drug selected from the group consisting of a CFTR function improving agent and an ENaC inhibitor are simultaneously administered in the body. It is not necessary to be present in the body for a certain period of time (for example, one month, preferably one week, more preferably several days, even more preferably one day). Sometimes the other active ingredient may have disappeared from the body.
  • Examples of the dosage form of the medicament of the present invention include, for example, 1) (a) a compound represented by the formula (I) or a pharmaceutically acceptable salt thereof, and (b) a CFTR function improving agent and an ENaC inhibitor.
  • Administration of a single preparation containing at least one drug selected from the group 2) (a) a compound represented by the formula (I) or a pharmaceutically acceptable salt thereof, and (b) a CFTR function improving agent and Simultaneous administration by the same administration route of two formulations obtained by separately formulating at least one drug selected from the group consisting of ENaC inhibitors, 3) (a) a compound represented by the formula (I) or Time difference in the same administration route between two formulations obtained by separately formulating the pharmaceutically acceptable salt thereof and (b) at least one drug selected from the group consisting of CFTR function improving agents and ENaC inhibitors Administration in the ) (A) separately formulating a compound represented by the formula (I) or a pharmaceutically acceptable salt thereof and (b) at least one drug selected
  • Administration of the two preparations obtained by different administration routes 5) (a) a compound represented by the formula (I) or a pharmaceutically acceptable salt thereof, and (b) a CFTR function-improving agent and ENaC inhibition Examples include administration of two formulations obtained by separately formulating at least one drug selected from the group consisting of drugs with different administration routes at different times.
  • kits containing them when two different preparations are used, a kit containing them may be used.
  • administer the drug means that the gene encoding the antisense oligonucleotide or CFTR is introduced directly or by using a viral or non-viral vector. Or repairing the abnormality of the gene encoding CFTR by a genome editing technique such as CRISPR / Cas9.
  • one embodiment of the present invention provides (a) a compound represented by the formula (I) which is administered in combination with at least one drug independently selected from the group consisting of a CFTR function improving agent and an ENaC inhibitor.
  • the compound or a pharmaceutically acceptable salt thereof means (b) CFTR function improving agents and ENaC inhibitors.
  • administering to a patient who has been treated with at least one drug selected from the group consisting of:
  • the medicament according to the present invention is (a) at least one selected from the group consisting of a compound represented by the formula (I) or a pharmaceutically acceptable salt thereof and / or (b) a CFTR function improving agent and an ENaC inhibitor.
  • carriers When used as tablets, carriers include excipients such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid, etc .; water, ethanol, propanol, simple syrup, glucose Liquid, starch liquid, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidone, and other binders; dried starch, sodium alginate, agar powder, laminaran powder, sodium hydrogen carbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid Disintegrators such as esters, sodium lauryl sulfate, stearic acid monoglyceride, starch, lactose; disintegration inhibitors such as sucrose, stearin, cocoa butter, hydrogenated oil; quaternary ammonium salts, sodium lauryl sulfate Absorbents such as glycerin and starch; Adsorbents
  • excipients such as glucose, lactose, cocoa butter, starch, hydrogenated vegetable oil, kaolin, talc; binders such as gum arabic powder, tragacanth powder, gelatin, ethanol; laminaran; Disintegrators such as agar can be used.
  • those conventionally known in the art can be widely used as the carrier, and examples thereof include polyethylene glycol, cocoa butter, higher alcohols, higher alcohol esters, gelatin, and semi-synthetic glycerides.
  • ⁇ When used as an injection, it can be used as a liquid, emulsion or suspension. These solutions, emulsions or suspensions are preferably sterilized and isotonic with blood.
  • the solvent used in the production of these liquid preparations, emulsions or suspensions is not particularly limited as long as it can be used as a diluent for medical use.
  • the preparation may contain a sufficient amount of salt, glucose or glycerin to prepare an isotonic solution, and may also contain ordinary solubilizing agents, buffers, soothing agents and the like. You may go out.
  • the above-mentioned preparations may contain a coloring agent, a preservative, a flavor, a flavoring agent, a sweetening agent, and the like, if necessary, and may further contain other pharmaceuticals.
  • the amount of the active ingredient compound contained in the above preparation is not particularly limited and may be appropriately selected in a wide range, but usually contains 0.5 to 70% by weight, preferably 1 to 30% by weight of the whole composition.
  • the amount used depends on the symptoms, age, etc. of the patient (warm-blooded animal, especially human), but in the case of oral administration, the lower limit is 0.01 mg / kg body weight (preferably 0.1 mg / kg) per dose. / Kg body weight), 500 mg / kg body weight (preferably 100 mg / kg body weight) as an upper limit, and 0.001 mg / kg body weight (preferably, once per intravenous administration) 0.01 mg / kg body weight), and, as an upper limit, 50 mg / kg body weight (preferably 10 mg / kg body weight) is desirably administered once or several times a day depending on the symptoms.
  • Kalydeco registered trademark
  • Ivacaftor usually 150 mg for children and adults aged 6 years or older, 75 mg for children aged 2 to 6 years older than 14 kg, and 2 to 6 years for a body weight of 14 kg or less.
  • a preferred example is oral administration of a child of less than 50 mg every 12 hours, but it may be adjusted as appropriate according to the patient's condition.
  • Orkambi registered trademark
  • adult Ivacaftor125 mg and Lumacaftor200 mg for 12-year-old and older
  • the type of cystic fibrosis to be treated is not limited, but is particularly suitable for patients with class III and class IV mutations of CFTR when used in combination with CFTR potentiator, and has class II mutation when used in combination with CFTR corrector. Particularly suitable for patients.
  • Mg milligram
  • g gram
  • ⁇ l microliter
  • ml milliliter
  • L liter
  • M molarity
  • MHz megahertz
  • nuclear magnetic resonance (hereinafter, 1 H-NMR: 400 MHz) spectra were described using chemical values of ⁇ (ppm) with tetramethylsilane as a standard substance.
  • the fission pattern was indicated by s for singlet, d for doublet, t for triplet, q for quadruple, spt for sevenfold, m for multiplet, and br for broad.
  • RVIII reflection type powder X-ray diffractometer
  • CuK ⁇ CuK ⁇
  • ⁇ 1.54 angstroms
  • the sample was measured using a non-reflective sample holder (tube).
  • the moisture was measured using a Karl Fischer moisture meter (coulometric titration method MKC-610) manufactured by Kyoto Electronics Industry Co., Ltd. (Anolyte: Hydranal Coulomat AG (Sigma Aldrich), Catholyte: Hydranal Coulomat CG (Sigma Aldrich) )).
  • TG / DTA6200 manufactured by Hitachi High-Tech Science Corp. was used (heating rate: 10 ° C / min, atmosphere gas: nitrogen, nitrogen gas flow rate: 200 ml / min).
  • Step 2 2- (tert-butoxymethyl) -5- (2-chlorobenzyl) -6-methylpyrimidin-4 (3H) -one N, N-dimethylformamide of the compound (5.6 g) obtained in the above step 1
  • To the (30 ml) solution were added the compound obtained in Step 1 of Reference Example 1 (5.8 g) and 1,8-diazabicyclo [5.4.0] undec-7-ene (10.5 ml). The mixture was stirred at 75 ° C. for 26 hours. After cooling, a saturated aqueous solution of sodium hydrogen carbonate was added to the reaction solution, and the mixture was extracted with ethyl acetate.
  • Step 3 2- (tert-butoxymethyl) -4-chloro-5- (2-chlorobenzyl) -6-methylpyrimidine
  • Triphenylphosphine (6.9 g) and trichloroacetonitrile (0.88 ml) were added and the mixture was stirred at 120 ° C. for 1 hour. After cooling, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with chloroform. The extract was washed with saturated saline and dried over anhydrous sodium sulfate.
  • Step 4 2- (tert-butoxymethyl) -5- (2-chlorobenzyl) -4-methoxy-6-methylpyrimidine
  • methanol 4 ml
  • Cesium (1.44 g) was added and the mixture was stirred at room temperature for 2 days.
  • Water was added to the reaction solution, which was extracted with ethyl acetate. The extract was washed with saturated saline and dried over anhydrous sodium sulfate.
  • Step 5 (5- (2-chlorobenzyl) -4-methoxy-6-methylpyrimidin-2-yl) methanol
  • trifluoroacetic acid (2 ml)
  • a mixture was obtained.
  • Water was added to the reaction solution, which was extracted with ethyl acetate.
  • the extract was washed successively with a saturated aqueous solution of sodium hydrogen carbonate and a saturated saline solution, and then dried over anhydrous sodium sulfate.
  • Step 6 5- (2-chlorobenzyl) -4-methoxy-6-methylpyrimidine-2-carboxylic acid
  • acetonitrile 6 ml
  • sodium phosphate buffer (0.67 M, pH 6.7, 4 ml)
  • (2,2,6,6-tetramethylpiperidin-1-yl) oxyl 31 mg
  • Step 1 5- (2-Chlorobenzyl) -4-methoxy-6-methylpyrimidine-2-carboxylic acid 3/2 hydrate
  • 2-propanol (1. 8 ml) and water (0.2 ml) were added and the mixture was stirred at 95 ° C. for 15 minutes. After cooling to room temperature, the mixture was stirred at room temperature overnight. The precipitate was collected by filtration, washed with water, and dried to give the title compound (188 mg).
  • Example 7 5- (2-chlorobenzyl) -4-methoxy-6-methylpyrimidine-2-carboxylic acid sodium salt
  • ethanol 5042 ⁇ l
  • a 1.0 mol / l sodium hydroxide ethanol solution 982 ⁇ l was added.
  • the mixture was stirred at 40 ° C. for about 24 hours, then left at room temperature for about 0.5 hour.
  • the solid was collected by filtration and dried at room temperature overnight to give the title compound (289.98 mg, recovery 97%).
  • Example 8 5- (2-chlorobenzyl) -4-methoxy-6-methylpyrimidine-2-carboxylic acid tert-butylamine salt To a compound (300.90 mg) obtained in the same manner as in Example 2 was added acetone (5913 ⁇ l). In addition, tert-butylamine (105 ⁇ l) was added. The mixture was stirred at 40 ° C. for about 24 hours, then left at room temperature for about 0.5 hour. The solid was collected by filtration and dried overnight at room temperature to give the title compound (332.74 mg, 97% recovery).
  • Example 9 5- (2-chlorobenzyl) -4-methoxy-6-methylpyrimidine-2-carboxylic acid diisopropylamine salt To a compound (300.05 mg) obtained in the same manner as in Example 2 was added acetone (5863 ⁇ l). , Diisopropylamine (138 ⁇ l). The mixture was stirred at 40 ° C. for about 24 hours, then left at room temperature for about 0.5 hour. The solid was collected by filtration and dried overnight at room temperature to give the title compound (353.95 mg, 96% recovery).
  • the chloride ion secretion ability was calculated by dividing the average of the RFU values for 10 seconds from 110 seconds to 120 seconds from the start of measurement by the average value from 0 seconds to 34 seconds (basal value).
  • the chloride ion secretion activity (EC 50 value) of the test compound was calculated from the chloride ion secretion ability at each concentration of the serially diluted test compound at each concentration. The concentration was calculated as the concentration of the test compound giving a% secretory ability.
  • the chloride ion secretion activity (EC 50 value) of the compound of Example 1 was 10.0 nM.
  • Test Example 2 Effect of GPR39 knockdown on chloride secretion by test compound It was confirmed by gene knockdown that chloride secretion by the test compound observed in Test Example 1 was a GPR39-mediated reaction. That is, CuFi-1 cells cultured in Pneumacult-EX (STEMCELL Technologies) were seeded on a 96-well plate at 3 ⁇ 10 4 cells / 100 ⁇ l / well, and Lipofectamine RNAiMAX (ThermoFisherFisherFisherFisherFisherFisherFisherFisherFisherFisherFisher.com) using Lipofectamine RNAiMAX (MISSION siRNA SASI_Hs02_00332000, SASI_Hs02_00332001, Sigma-Aldrich) or control siRNA (Ambion Silencer Select, Thermo Fisher Scientific) was added at 1 pmol / 10 ⁇ l / w, followed by 1 pmol / 10 l culture.
  • N- (Ethoxycarbonylmethyl) -6-methoxyquinolinium bromide (MQAE) diluted with the medium was added at 10 ⁇ l / well to a final concentration of 5 mM. After adding MQAE, the cells were cultured overnight and passively loaded. Thereafter, washing and measurement of chloride ion secretion ability were performed in the same manner as in Test Example 1.
  • GPR39 gene expression was analyzed using RNA extracted from the well in which the same operation was performed. That is, total RNA is extracted from the cells using RNAiso Plus (Takara Bio Inc.), purified using RNeasy Micro Kit (Qiagen), and then purified using High Capacity cDNA Reverse Transcription Kit (Thermo Fisher cDNA Inc.).
  • a medium in which a test compound and zinc (final concentration: 10 ⁇ M) were dissolved was added to the upper layer at a volume of 100 ⁇ l / well, and a medium in which a test compound and zinc (final concentration: 10 ⁇ M) were dissolved was added to the lower layer at a volume of 500 ⁇ l / well.
  • the weight of the upper layer medium 72 hours after the addition of the test compound was measured with an electronic balance to confirm the water transfer effect of the test compound.
  • the effects of VX-809 (lumacaftor) alone (Selleck Chemicals) and VX-809 (lumacaftor) / VX-770 (ivacaftor) combination were also examined.
  • the results for the above three types of cells using the compound of Example 1 as the test compound are shown in FIGS.
  • the compound of Example 1 moved water in a concentration-dependent manner. The effect was similar to that of VX-809 alone or the combination of VX-809 / VX-770.
  • the compound of Example 1 also exhibited an activity equivalent to that of the ⁇ F508zhomozygus mutation in mutations other than the ⁇ F508 homozygus mutation (2184 ⁇ A + W1282X (class I mutation)) and N1303K heterozygos, and could be effective without depending on the mutation.
  • the ⁇ F508zhomozygus mutation in mutations other than the ⁇ F508 homozygus mutation (2184 ⁇ A + W1282X (class I mutation)) and N1303K heterozygos, and could be effective without depending on the mutation.
  • VX-809 / VX-770 had a weak effect on 2184 ⁇ A + W1282X (class I mutation), and it was considered that the effect was dependent on the mutation.
  • the effect of the compound of Example 1 on 2184 ⁇ A + W1282X (class I mutation) was significant as compared with the combination of VX-809 / VX-770.
  • Test Example 4 Effect of Combination of Test Compound with VX-809 / VX-770 Combination in ALI Assay Using Water Movement as Index ⁇ F508 homozygous Mutant ALI culture system using the compound of Example 1 and VX- The effect of the combination of 809 (lumacaftor) / VX-770 (ivacaftor) with the combination was examined. The combined effect was examined in the same manner as in Test Example 3. That is, cells obtained by ALI-cultured primary bronchial epithelial cells derived from a cystic fibrosis patient having a ⁇ F508 homozygous mutation (MucilAir-CF TM ) were purchased from Epithelix.
  • FIG. 6 shows the results of using the compound of Example 1 as a test compound.
  • the mixture of VX-809 / VX-770 significantly moved water, similarly to the result of Test Example 3.
  • the compound of Example 1 was concentration-dependent on the water transfer amount of the mixture of VX-809 / VX-770, and Moisture was added additively. Therefore, the combined effect of the test compound with the combination of VX-809 / VX-770 was confirmed.
  • Example 3 the compound of Example 1 was not dependent on mutation in the ALI culture system. Because of the possibility of being effective, it is not limited to the combination of VX-809 / VX-770, but a drug having an action mechanism different from that of a GPR39 agonist, for example, other than the combination of VX-809 / VX-770 It is thought that a combination effect can be expected even in combination with a CFTR function improving drug or an ENaC inhibitor.
  • the compound represented by the formula (I) of the present invention or a pharmaceutically acceptable salt thereof has a strong chloride ion secretion action through GPR39 agonist action and transfers water. Since this compound can open a chloride channel different from CFTR which causes disease, it exhibits an excellent therapeutic effect when combined with a CFTR function improving agent or an ENaC inhibitor. Therefore, the medicament / therapeutic method using the compound of the present invention or a pharmaceutically acceptable salt thereof in combination with a CFTR function improving agent or an ENaC inhibitor can be carried out by any of class I to VI irrespective of the type of CFTR mutation. It is useful because it can also exert a therapeutic effect on fibrosis.

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Abstract

La présente invention aborde le problème de la fourniture d'un médicament qui est destiné aux fibroses kystiques qui se développent par la mutation d'un régulateur de conductance transmembranaire de la fibrose kystique (CFTR) qui est un type de canal du chlorure, et qui est apte à exprimer un effet thérapeutique pour toute fibrose kystique des classes I à VI, quel que soit le type de mutation du CFTR. La présente invention concerne une méthode médicale/de traitement caractérisée par l'administration d'une association de : (a) un composé représenté par la formule (I) ou un sel pharmaceutiquement acceptable de celui-ci ; et (b) un ou plusieurs médicaments sélectionnés individuellement dans le groupe constitué par un médicament améliorant la fonction du CFTR et un inhibiteur d'ENaC.
PCT/JP2019/024614 2018-06-22 2019-06-21 Agent thérapeutique contre une fibrose kystique Ceased WO2019245010A1 (fr)

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018124000A1 (fr) * 2016-12-27 2018-07-05 第一三共株式会社 Dérivé pyrimidine

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018124000A1 (fr) * 2016-12-27 2018-07-05 第一三共株式会社 Dérivé pyrimidine

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