WO2016027781A1 - 単環ピリジン誘導体の塩およびその結晶 - Google Patents
単環ピリジン誘導体の塩およびその結晶 Download PDFInfo
- Publication number
- WO2016027781A1 WO2016027781A1 PCT/JP2015/073047 JP2015073047W WO2016027781A1 WO 2016027781 A1 WO2016027781 A1 WO 2016027781A1 JP 2015073047 W JP2015073047 W JP 2015073047W WO 2016027781 A1 WO2016027781 A1 WO 2016027781A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- ppm
- methoxyethoxy
- methyl
- oxy
- indole
- Prior art date
Links
- IBHOLSBDZMIPPT-UHFFFAOYSA-N CNC([n](ccc1c2)c1cc(OCCOC)c2Oc1cc(NC(c2ccc(C3CCN(CCO)CC3)cc2)=O)ncc1)=O Chemical compound CNC([n](ccc1c2)c1cc(OCCOC)c2Oc1cc(NC(c2ccc(C3CCN(CCO)CC3)cc2)=O)ncc1)=O IBHOLSBDZMIPPT-UHFFFAOYSA-N 0.000 description 2
- LDJQILNZENZMON-UHFFFAOYSA-N CNC([n](ccc1c2)c1cc(OCCOC)c2Oc1cc(NC(c2ccc(C3CCNCC3)cc2)=O)ncc1)=O Chemical compound CNC([n](ccc1c2)c1cc(OCCOC)c2Oc1cc(NC(c2ccc(C3CCNCC3)cc2)=O)ncc1)=O LDJQILNZENZMON-UHFFFAOYSA-N 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- 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
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C55/00—Saturated compounds having more than one carboxyl group bound to acyclic carbon atoms
- C07C55/02—Dicarboxylic acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C55/00—Saturated compounds having more than one carboxyl group bound to acyclic carbon atoms
- C07C55/02—Dicarboxylic acids
- C07C55/10—Succinic acid
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Definitions
- the present invention relates to a salt of a monocyclic pyridine derivative having an FGFR inhibitory action and a crystal thereof.
- FGF fibroblast growth factor
- FGFR FGF receptors
- FGFR FGF receptors
- FGFR is composed of three types: an extracellular domain, a transmembrane domain, and an intracellular tyrosine kinase domain. FGF binds to the FGFR extracellular domain to form a receptor dimer.
- MAPK mitogen-activated protein kinase
- ERK extracellular signal-regulated kinase
- PI3K phosphatidylinositol 3-kinase
- FGF / FGFR signal abnormality is induced by FGF production enhancement, FGFR gene amplification, FGFR overexpression, FGFR fusion protein formation, FGFR mutation, etc. It has been reported that various cancers such as endometrial cancer and prostate cancer are caused (Non-patent Document 1).
- Non-small cell lung cancer, small cell lung cancer, ovarian cancer, sarcoma, colon cancer, melanoma, glioblastoma, astrocytoma, or head and neck cancer as a cancer with FGF / FGFR signal abnormality (Non-patent Document 2) 3), thyroid cancer (Non-patent document 4), pancreatic cancer (Non-patent documents 5 and 6), liver cancer (Non-patent document 7), skin cancer (Non-patent document 8), renal cancer (Non-patent document 9) And squamous cell carcinoma of the lung (Non-Patent Documents 10, 11, and 12) have been reported.
- FGF / FGFR signal is a major angiogenesis signal along with VEGF (vascular endothelial growth factor) / KDR (kinase-insert domain-containing receptor) signal, and also cancer stromal cells (fibroblasts).
- VEGF vascular endothelial growth factor
- KDR kinase-insert domain-containing receptor
- an FGFR inhibitor targeting FGF / FGFR signal is expected as an antitumor agent based on a suppressive action on the abnormal signal or angiogenic signal in cancer with abnormal FGF / FGFR signal.
- selective FGFR inhibitors that are considered to be less susceptible to other signal confronting effects, such as FGFR1, FGFR2 and FGFR3, which are clearly different in structure from the compounds of the present invention.
- Patent Document 3 discloses a pyrimidine derivative, but does not disclose an inhibitory action on signal abnormality of FGF / FGFR signal.
- Patent Document 4 discloses a pyridine derivative or a pyrimidine derivative that suppresses angiogenesis induced by VEGF and FGF. However, these documents do not disclose the compounds according to the present invention.
- a compound represented by the following formula (I) (5-( ⁇ 2-[( ⁇ 4- [1- (2-hydroxyethyl) piperidin-4-yl] phenyl ⁇ carbonyl) amino] pyridin-4-yl ⁇ oxy ) -6- (2-methoxyethoxy) -N-methyl-1H-indole-1-carboxamide, hereinafter referred to as Compound (I)) has FGFR1, FGFR2 and FGFR3 inhibitory activity.
- the properties of compounds used as pharmaceuticals and salts thereof and crystals thereof have a great influence on the bioavailability of drugs, the purity of drug substances, the formulation of pharmaceuticals, and the like. Accordingly, an object of the present invention is to provide a salt of Compound (I) and a crystal thereof having applicability as an active pharmaceutical ingredient.
- the salt of compound (I) and the crystal thereof provided by the present invention have properties as shown in Examples, and also have hygroscopic characteristics as shown in the data of Test Examples described later. It can be used as a drug substance for pharmaceuticals.
- FIG. 1 is a powder X-ray diffraction pattern of the crystal of compound (I) ⁇ 1.5 succinate obtained in Example 1.
- FIG. The horizontal axis indicates the diffraction angle (2 ⁇ ), and the vertical axis indicates the peak intensity.
- FIG. 2 is a powder X-ray diffraction pattern of the crystal ( ⁇ ) of compound (I) ⁇ 0.5 succinate obtained in Example 2.
- the horizontal axis indicates the diffraction angle (2 ⁇ ), and the vertical axis indicates the peak intensity.
- FIG. 3 is a powder X-ray diffraction pattern of the crystal of compound (I) ⁇ maleate obtained in Example 3.
- the horizontal axis indicates the diffraction angle (2 ⁇ ), and the vertical axis indicates the peak intensity.
- FIG. 4 is a 13C solid state NMR spectrum of the crystal of compound (I) ⁇ 1.5 succinate obtained in Example 1.
- FIG. FIG. 5 is a graph showing the hygroscopicity of the crystals of compound (I) ⁇ 1.5 succinate obtained in Example 1. The horizontal axis represents relative humidity, and the vertical axis represents weight change.
- FIG. 6 is a powder X-ray diffraction pattern of the compound (I) ⁇ free crystal (Free ⁇ Form A) obtained in Production Example 1-15. The horizontal axis indicates the diffraction angle (2 ⁇ ), and the vertical axis indicates the peak intensity.
- FIG. 7 is a powder X-ray diffraction pattern of the compound (I) ⁇ free form crystal (Free Form B) obtained in Reference Example 1.
- FIG. 8 is a powder X-ray diffraction pattern of the compound (I) -free crystal obtained in Reference Example 2 (Free Form Hydrate). The horizontal axis indicates the diffraction angle (2 ⁇ ), and the vertical axis indicates the peak intensity.
- FIG. 9 is a powder X-ray diffraction pattern of the compound (I) mesylate crystal obtained in Reference Example 3. The horizontal axis indicates the diffraction angle (2 ⁇ ), and the vertical axis indicates the peak intensity.
- FIG. 10 is a powder X-ray diffraction pattern of the compound (I) -tosylate crystal obtained in Reference Example 4.
- FIG. 11 is a powder X-ray diffraction pattern of crystals of compound (I) .benzoate obtained in Reference Example 5.
- the horizontal axis indicates the diffraction angle (2 ⁇ ), and the vertical axis indicates the peak intensity.
- FIG. 12 is a powder X-ray diffraction pattern of the crystal of compound (I) • fumarate obtained in Reference Example 6.
- the horizontal axis indicates the diffraction angle (2 ⁇ ), and the vertical axis indicates the peak intensity.
- FIG. 13 is a powder X-ray diffraction pattern of the crystal ( ⁇ ) of compound (I) ⁇ 0.5 succinate obtained in Example 4.
- the horizontal axis indicates the diffraction angle (2 ⁇ ), and the vertical axis indicates the peak intensity.
- 14 is a powder X-ray diffraction pattern of compound (I) ⁇ 0.5 succinate crystal ( ⁇ ) obtained in Example 5.
- FIG. The horizontal axis indicates the diffraction angle (2 ⁇ ), and the vertical axis indicates the peak intensity.
- FIG. 15 is an amorphous powder X-ray diffraction pattern of the compound (I) ⁇ 1.5 succinate obtained in Example 6.
- the horizontal axis indicates the diffraction angle (2 ⁇ ), and the vertical axis indicates the peak intensity.
- salt means a chemical substance composed of compound (I), which is a basic component, and an acid having a specific equivalent number with respect to compound (I).
- salts used in the present specification include a salt with an inorganic acid, a salt with an organic acid, a salt with an acidic amino acid, and the like, and among them, a pharmaceutically acceptable salt is preferable.
- salts with inorganic acids include, for example, salts with hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.
- salts with organic acids include, for example, acetic acid, succinic acid, fumaric acid.
- Acid maleic acid, tartaric acid, malic acid, citric acid, lactic acid, stearic acid, salts with organic carboxylic acids such as benzoic acid, methanesulfonic acid (mesic acid), ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid
- organic carboxylic acids such as benzoic acid, methanesulfonic acid (mesic acid), ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid
- organic carboxylic acids such as benzoic acid, methanesulfonic acid (mesic acid), ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid
- examples thereof include salts with organic sulfonic acids such as (tosylic acid), among which succinic acid and maleic acid are preferable, and succinic acid is particularly
- salts with acidic amino acids include salts with aspartic acid, glutamic acid and the like.
- the salt of the present invention may be an anhydride, hydrate or solvate.
- the hydrate or solvate refers to a solid formed by combining Compound (I) or a salt thereof with a water molecule or a solvent molecule, respectively, and the solid may be a crystal.
- ketone solvents such as acetone, 2-butanone and cyclohexanone
- ester solvents such as methyl acetate and ethyl acetate
- ether solvents such as alcohol solvents such as methanol, ethanol, 1-propanol and isopropanol
- polar solvents such as N-methyl-2-pyrrolidone, N, N-dimethylformamide and dimethyl sulfoxide.
- the number of water molecules or solvent molecules for compound (I) or a salt thereof is not particularly limited, and may be one molecule or two molecules, for example.
- crystal refers to a crystal of compound (I) or a salt thereof.
- a crystal of compound (I) ⁇ 1.5 succinate is a crystal of a salt formed from compound (I) and succinic acid, and succinic acid is added to one molecule of compound (I). It means a salt crystal containing 1.5 molecules.
- the diffraction peaks in the powder X-ray diffraction described above are: compound (I) ⁇ 1.5 succinate crystal, compound (I) ⁇ 0.5 succinate crystal ( ⁇ ) and ( ⁇ ), compound (I) )-It is unique to each maleate crystal and is a diffraction peak characteristic of the crystal.
- the above diffraction angle value includes a numerical value within a range of about ⁇ 0.2 °. Need to be understood. Therefore, in a specific salt, not only a crystal in which the diffraction angle of a peak in powder X-ray diffraction completely matches, but also a crystal in which the diffraction angle of a peak matches with an error of about ⁇ 0.2 ° is the same. include.
- “having a diffraction peak at a diffraction angle (2 ⁇ ⁇ 0.2 °) of 22.4 °” means “having a diffraction peak at a diffraction angle (2 ⁇ ) of 22.2 ° to 22.6 °. The same applies to other diffraction angles.
- the peak intensity or half-value width of the diffraction angle (2 ⁇ ) in powder X-ray diffraction is the difference in measurement conditions and the size and shape of each particle of a powder crystal used as a measurement sample even if the crystal form is the same. Due to variations, it varies from measurement to measurement, and a constant peak intensity or full width at half maximum is not always indicated. Therefore, in the comparison of powder X-ray diffraction patterns, even if there is a difference in peak intensity or half-value width at the same diffraction angle (2 ⁇ ), the difference does not mean that the difference is derived from different crystal forms.
- the crystal of the salt of the powder X-ray diffraction pattern having such a difference with respect to the diffraction peak characteristic of the crystal of the specific salt of the present invention has the same crystal form as the crystal of the salt of the present invention. It means that there is.
- “having the powder X-ray diffraction pattern of FIG. 1” means not only the case where the powder X-ray diffraction pattern having a characteristic diffraction peak completely matches the pattern shown in FIG. This means that the powder X-ray diffraction pattern shown in FIG. 1 is obtained even in the case of a powder X-ray diffraction pattern having the same diffraction angle but different peak intensity or half width. Therefore, it means that all crystals having such a powder X-ray diffraction pattern are the same crystals as the crystal of the present invention.
- chemical shift ( ⁇ 0.5 ppm) 27.1 ppm, 34.8 ppm, 108.5 ppm, 155.1 ppm and 179.9 ppm means “normal measurement conditions or substantially the same as the present specification. 13 C solid state NMR spectra were measured under the same conditions, and peaks substantially equivalent to chemical shifts ( ⁇ 0.5 ppm) of 27.1 ppm, 34.8 ppm, 108.5 ppm, 155.1 ppm and 179.9 ppm, respectively. It means "having”.
- the chemical shift (ppm) in a 13 C solid state NMR spectrum can cause an error within a range of ⁇ 0.5 ppm.
- the value of should be understood as including values in the range of about ⁇ 0.5 ppm. Therefore, the present invention includes not only crystals in which the chemical shift in the 13 C solid state NMR spectrum is completely matched but also crystals in which the chemical shift is matched with an error of about ⁇ 0.5 ppm.
- the salt of compound (I) according to the present invention can be obtained by a method for producing an ordinary salt. Specifically, for example, compound (I) is heated or suspended in a solvent as necessary to suspend or dissolve it, and then an acid is added to the resulting suspension or solution and cooled at room temperature or cooled. However, it can be produced by stirring or standing for several minutes to several days.
- the salt of the compound (I) can be obtained as a crystal or amorphous. Amorphous can also be obtained by subjecting these production methods to operations such as freeze-drying as necessary.
- solvent used here examples include alcohol solvents such as ethanol, 1-propanol and isopropanol; acetonitrile; ketone solvents such as acetone and 2-butanone; ester solvents such as ethyl acetate; saturated carbonization such as hexane and heptane.
- alcohol solvents such as ethanol, 1-propanol and isopropanol
- ketone solvents such as acetone and 2-butanone
- ester solvents such as ethyl acetate
- saturated carbonization such as hexane and heptane.
- hydrogen solvents examples of hydrogen solvents
- ether solvents such as t-butyl methyl ether, and water.
- Crystal of Compound (I) or a salt thereof can be produced by the above-described method for producing Compound (I) or a method for producing a salt thereof, or Compound (I) It can also be produced by dissolving I) or a salt thereof in a solvent by heating, cooling with stirring and crystallization.
- Compound (I) or a salt thereof used for crystallization may be in any form, and may be a solvate, hydrate, or anhydride, and may be amorphous or crystalline (from a plurality of crystal polymorphs). Or a mixture thereof.
- Solvents used for crystallization are, for example, alcohol solvents such as methanol, ethanol, isopropanol, 1-propanol; acetonitrile; amide solvents such as N, N-dimethylformamide; ester solvents such as ethyl acetate; hexane, heptane And saturated hydrocarbon solvents such as acetone; ketone solvents such as acetone and 2-butanone; ether solvents such as t-butyl methyl ether; and water. These solvents may be used alone or in combination of two or more.
- the amount of the solvent used can be appropriately selected with the lower limit being the amount in which the compound (I) or a salt thereof is dissolved by heating or the amount allowing the suspension to be stirred, and the upper limit being the amount that does not significantly reduce the yield of crystals. .
- seed crystals (such as crystals of desired compound (I) or a salt thereof) may or may not be added.
- the temperature at which the seed crystal is added is not particularly limited, but is preferably 0 to 80 ° C.
- the temperature at which compound (I) or a salt thereof is dissolved by heating may be appropriately selected according to the solvent, and the temperature at which compound (I) or a salt thereof is dissolved is preferably selected. It is the range of the temperature at which the reflux starts, and more preferably 55 to 80 ° C.
- Cooling during crystallization can give crystals containing different forms of crystals (polymorphs) when rapidly cooled, so it is desirable to adjust the cooling rate appropriately in consideration of the effects on crystal quality and particle size.
- cooling is performed at a rate of 5 to 40 ° C./hour, for example. More preferable is cooling at a rate of 5 to 25 ° C./hour, for example.
- the final crystallization temperature can be appropriately selected from the yield and quality of crystals, but is preferably -25 to 30 ° C.
- the crystallized crystal is separated by a normal filtration operation. If necessary, the crystal separated by filtration is washed with a solvent, and further dried to obtain a target crystal.
- a solvent used for washing the crystals, the same crystallization solvent can be used.
- Preferable examples include ethanol, acetone, 2-butanone, ethyl acetate, diethyl ether, t-butyl methyl ether, and hexane. These solvents may be used alone or in combination of two or more.
- the crystals separated by the filtration operation can be appropriately dried by being left in the air or a nitrogen stream, or by heating.
- the drying time may be appropriately selected according to the production amount, drying apparatus, drying temperature, etc. until the residual solvent falls below a predetermined amount. Moreover, drying can be performed under ventilation or under reduced pressure. The degree of vacuum may be appropriately selected according to the production amount, the drying device, the drying temperature, and the like. The obtained crystals can be left in the air after drying, if necessary.
- the salt of Compound (I) and crystals thereof can be formulated by a conventional method.
- the dosage form include oral preparations (tablets, granules, powders, capsules, syrups, etc.), injections ( For intravenous administration, intramuscular administration, subcutaneous administration, intraperitoneal administration, etc.), external preparations (transdermal absorption preparations (ointments, patches, etc.), eye drops, nasal drops, suppositories, etc.) be able to.
- an excipient When producing an oral solid preparation, an excipient, a binder, a disintegrant, a lubricant, a coloring agent, etc. are added to the salt of compound (I) or a crystal thereof as necessary.
- a binder When producing an oral solid preparation, an excipient, a binder, a disintegrant, a lubricant, a coloring agent, etc. are added to the salt of compound (I) or a crystal thereof as necessary.
- tablets, granules, powders and capsules can be produced. Tablets, granules, powders, capsules and the like may be coated as necessary.
- excipient for example, lactose, crystalline cellulose and the like, as the binder, for example, hydroxypropyl cellulose and the like, as the disintegrant, for example, croscarmellose sodium and the like, as the lubricant, for example,
- the colorant include magnesium stearate, titanium oxide, and the like
- the coating agent include, but are not limited to, hydroxypropylmethylcellulose and the like.
- a pH adjusting agent is added to the salt of compound (I) or a crystal thereof.
- a buffer, a suspending agent, a solubilizing agent, an antioxidant, a preservative (preservative), an isotonic agent and the like can be added to produce an injection by a conventional method. Alternatively, it may be freeze-dried to obtain a freeze-dried preparation that is dissolved at the time of use.
- pH adjusters and buffers include organic acids or inorganic acids and / or pharmaceutically acceptable salts thereof, and examples of suspending agents include hydroxypropyl cellulose and the like as solubilizers.
- polysorbate 80 and the like as an antioxidant, for example, ⁇ -tocopherol and the like, as preservatives, for example, methyl paraoxybenzoate, ethyl paraoxybenzoate and the like, and as an isotonic agent, for example , Glucose and the like can be mentioned, but are not limited thereto.
- These injections can usually contain any amount of the salt of compound (I) or a crystal thereof as long as it shows a medicinal effect that can be used as a medicine.
- a base material is added to the salt of compound (I) or a crystal thereof, and if necessary, for example, the above-mentioned preservative, pH adjuster, antioxidant, coloring agent, etc.
- transdermal preparations ovalments, patches, etc.
- eye drops nasal drops, suppositories and the like
- the base material to be used for example, various raw materials usually used for pharmaceuticals, quasi drugs, cosmetics and the like can be used.
- animal and vegetable oils for example, animal and vegetable oils, mineral oils, ester oils, waxes, emulsifiers, higher alcohols, fatty acids, silicone oils, surfactants, phospholipids, alcohols, polyhydric alcohols, water-soluble polymers And raw materials such as minerals, clay minerals and purified water.
- These external preparations can usually contain any amount of a salt of compound (I) or a crystal thereof as long as it shows a medicinal effect that can be used as a pharmaceutical product.
- the dosage of the salt of Compound (I) or crystals thereof varies depending on the degree of symptoms, age, sex, body weight, dosage form / salt type, specific type of disease, etc., without causing unacceptable side effects. Although it is not limited as long as the maximum dose of the drug that can be administered is not exceeded, in general, in the case of an adult, about 30 ⁇ g to 10 g, for example, 100 ⁇ g to 5 g, further about 100 ⁇ g to 1 g, for example, about 30 ⁇ g 1 g, for example, 100 ⁇ g to 500 mg, and further, for example, 100 ⁇ g to 300 mg are administered once or in several divided doses.
- the compound according to the present invention can be produced, for example, by the methods described in the following production examples and examples. However, these are illustrative, and the compound according to the present invention is not limited to the following specific examples in any case.
- the 13 C solid state NMR spectrum of the crystal was measured under the following conditions. The result is shown in FIG. Measuring condition use device: AVANCE400 (manufactured by BRUKER) Measurement temperature: Room temperature (22 ° C) Reference substance: Glycine (External standard: 176.03 ppm) Measurement nucleus: 13C (100.6248425MHz) Pulse repetition time: 3 seconds Pulse mode: TOSS measurement
- silica gel 60 (Kanto Chemicals) or Presep Silica Gel (WAKO) was used as the silica gel for purification used in silica gel column chromatography.
- the silica gel for purification used in NH silica gel column chromatography was NH silica gel (Fuji Silysia Chemical LTD.) Or Hi-Flash Column Amino (YAMAZENE CORPORATION).
- the proton nuclear magnetic resonance spectrum was measured using a Varian Mercury 400, Varian Mercury Plus 400, Varian INOVA 500 or Avance 600 MHz (Bruker) at 400 MHz unless otherwise specified.
- the chemical shift of the proton nuclear magnetic resonance spectrum is recorded in ⁇ units (ppm) relative to tetramethylsilane, and the coupling constant is recorded in hertz (Hz).
- the abbreviations of the division pattern are as follows. s: singlet, d: doublet, t: triplet, m: multiplet, brs: broad singlet.
- the aqueous layer was extracted with ethyl acetate (100 mL), and the organic layers were combined and washed with saturated aqueous sodium hydrogen carbonate solution (100 mL), water (100 mL), and then saturated brine (50 mL). The organic layer was dried over anhydrous magnesium sulfate and the solvent was distilled off to obtain the title compound (12.3 g, 98%).
- the reaction mixture was poured into ice, and ethyl acetate (1 L) and water (1 L) were added to separate the layers.
- the aqueous layer was extracted twice with ethyl acetate (1 L), and then the organic layer was washed twice with water (1 L) followed by saturated brine (500 mL).
- the organic layer was dried over anhydrous magnesium sulfate and the solvent was distilled off.
- Ethyl acetate was added to the concentrated residue, and the product was filtered and washed with ethyl acetate to obtain the title compound (9.09 g, 61%).
- the crude product (23.0 g) was suspended in methanol (500 mL), 10% palladium-carbon (50% water-containing product) (8 g) was added at room temperature, and the mixture was stirred under a hydrogen atmosphere for 6 hr.
- the reaction solution was partitioned by adding water and ethyl acetate at room temperature.
- the aqueous layer was extracted 3 times with ethyl acetate, and the combined organic layers were washed with water.
- the organic layer was dried over anhydrous sodium sulfate.
- the target fraction was concentrated under reduced pressure to obtain the title compound (3.45 g, 53%).
- the aqueous layer was extracted 3 times with ethyl acetate, and the combined organic layers were dried over anhydrous sodium sulfate.
- Phenyl methyl carbamate (1.97 g, 13.0 mmol) described in Production Example 1-2 was added, and the mixture was stirred at room temperature for 1 hour.
- the reaction mixture was cooled to 0 ° C., and partitioned by adding ethyl acetate and water.
- the aqueous layer was extracted twice with ethyl acetate, sodium chloride was added to the aqueous layer and extracted three times with ethyl acetate.
- the combined organic layers were dried over anhydrous sodium sulfate.
- the target fraction was concentrated under reduced pressure, ethyl acetate was added, and the precipitate was collected by filtration and washed to obtain the title compound (2.23 g, 72%).
- reaction mixture was filtered through a glass filter lined with anhydrous sodium sulfate, washed with dichloromethane, and the filtrate was prepared according to 5-[(2-aminopyridin-4-yl) oxy] -6- (2 -Methoxyethoxy) -N-methyl-1H-indole-1-carboxamide (0.95 g, 2.67 mmol), triethylamine (1.86 mL, 13.3 mmol), 4-dimethylaminopyridine (16 mg, 0.133 mmol), To a mixture of N, N-dimethylformamide (3 mL) and dichloromethane (20 mL) was added at 0 ° C.
- Acetaldehyde (34.4 mg, 0.57 mmol) was added and stirred at room temperature for 2 hours.
- the reaction mixture was partitioned by adding a saturated aqueous sodium hydrogen carbonate solution and ethyl acetate.
- the aqueous layer was extracted with ethyl acetate, and the combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered.
- Example 4 The sample obtained in Example 4 was dried under reduced pressure for 3 days to give the title compound.
- the representative powder X-ray diffraction angle of the obtained compound is shown. (2 ⁇ ⁇ 0.2 °): 7.8 °, 10.8 °, 13.1 °, 14.2 °, 17.8 °, 21.5 °, 21.7 °, 23.4 °, 24 .5 ° and 29.0 °.
- the representative powder X-ray diffraction angle of the obtained compound is shown. (2 ⁇ ⁇ 0.2 °): 9.3 °, 13.9 °, 14.5 °, 15.8 °, 18.1 °, 19.4 °, 20.5 °, 21.3 °, 22 .6 ° and 26.2 °.
- Test example The following test examples were conducted, and the physical properties or pharmacological effects of the compound (I) or the salt of compound (I) described in Production Example 1-15 or a crystal thereof were examined.
- ADP-Glo TM Kinase Assay (promega V9102) was used for the kinase activity measurement. To the plate after the reaction, 25 ⁇ L of ADP-Glo reagent was added to each well and reacted at room temperature for 40 minutes to stop the kinase reaction, and the remaining ATP was depleted. Further, Kinase detection reagent was added and reacted at room temperature for 40 minutes to perform conversion from ADP to ATP, luciferase / luciferin coupling reaction, and luminescence reaction by ATP. The enzyme activity was evaluated by measuring the amount of luminescence in each well using Envision TM (Perkin Elmer Co., Ltd.).
- the light emission rate in the presence of the test substance is obtained by setting the light emission amount when the kinase protein is added without adding the test substance as 100% and the light emission amount when the test substance and the kinase protein are not added as 0%. It was.
- the concentration (IC 50 value) of the test substance necessary to inhibit the kinase activity by 50% was calculated from this luminescence amount rate.
- SNU-16 Growth Inhibition Assay Human gastric cancer cell line SNU-16 (ATCC Number CRL-5974) has been reported to have FGFR2 gene amplification (Cancer Res. 2008.68: 2340-2348).
- SNU-16 cells were maintained in a 5% CO 2 incubator (37 ° C.) using RPMI-1640 (WAKO 187-02021) medium containing 10% FBS and penicillin / streptomycin (WAKO 168-23191).
- RPMI-1640 WAKO 187-02021
- penicillin / streptomycin WAKO 168-23191
- the cells were cultured overnight in a 5% CO 2 incubator (37 ° C.). On the next day, 50 ⁇ L each of the test substance diluted in RPMI-1640 medium containing 10% FBS was added and cultured in a 5% CO 2 incubator (37 ° C.) for 3 days. 10 ⁇ L of Cell Counting Kit-8 (Dojindo Laboratories CK04) was added to each well, and the cells were cultured in a 5% CO 2 incubator (37 ° C.) for 1-2 hours for color development. Absorbance at 450 nm was measured by ENVISION TM (Perkin Elmer).
- Test Example 4 Antitumor Effect in Mouse SNU-16 Subcutaneous Transplant Model Human gastric cancer cell line SNU-16 cultured in RPMI-1640 medium containing 10% FBS and penicillin / streptomycin was treated with Hanks' Balanced Salt Solution (GIBCO # 24020 ) To a concentration of 1 ⁇ 10 8 cells / mL and mixed 1: 1 with MATRIGEL (BD Bioscience Cat # 354234) to prepare a cell suspension of 5 ⁇ 10 7 cells / ml. Nude mice aged 6-7 weeks (BALB / cAJcl-nu / nu, female, CLEA Japan, Inc.) were transplanted in a volume of 100 ⁇ L into the subcutaneous part of the right flank.
- Tumor volume (mm 3 ) major axis (mm) ⁇ minor axis (mm) ⁇ minor axis (mm) / 2
- the groups were divided so that the average values of the tumor volumes were almost equal.
- the test substance was dissolved in DMSO, Tween 80 was added, a 10-fold concentrated solution was prepared, and stored frozen.
- the test sample was orally administered once a day for 11 days at a dose volume of 20 mL / kg, and the control solvent was orally administered under the same conditions.
- the experiment was conducted with 5 animals per group.
- the weight ratio (RBW) of the last day to the weight of the first day is calculated.
- the test substance administration group in which the RBW of the test substance administration group / RBW of the control group was 0.9 or more was determined to be a safe administration group.
- the ratio (T / C) (%) of the tumor volume after test substance administration to the control tumor volume on the last day was calculated and shown in Table 3.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pyridine Compounds (AREA)
Abstract
Description
FGFは受容体チロシンキナーゼであるFGF受容体(FGFR:FGFR1、FGFR2、FGFR3、FGFR4)を介して、さまざまな生理機能を制御している。FGFRは細胞外ドメイン、膜貫通ドメインおよび細胞内チロシンキナーゼドメインの3種類から構成されている。FGFがFGFR細胞外ドメインと結合することで、受容体の二量体が形成される。その後、細胞内チロシンキナーゼが活性化された後、主にMAPK(mitogen-activated protein kinase)/ERK(extracellular signal-regulated kinase)経路やPI3K(phosphatidylinositol 3-kinase)/Akt経路を介して細胞内シグナルが伝達される。
したがって、FGF/FGFRシグナルを標的とするFGFR阻害剤は、FGF/FGFRシグナル異常を伴う癌において、そのシグナル異常に対する抑制作用や血管新生シグナルの抑制作用などに基づく抗腫瘍剤として期待されている。最近になって、他のシグナルの交絡的影響(Confronting effect)を受け難いと考えられる選択的FGFR阻害剤、例えば、本発明に係る化合物とは構造上明らかに異なっている、FGFR1、FGFR2およびFGFR3の選択的FGFR阻害剤が報告されている。しかし、ヒトの抗腫瘍剤としての開発において、選択的FGFR阻害剤は、FGF/FGFRシグナルとVEGF/KDRシグナルの両者を同時に標的とする抗腫瘍剤に遅れを取っており、未だ、市販されていない(非特許文献13、14、特許文献1、2)。特許文献3には、ピリミジン誘導体が開示されているが、FGF/FGFRシグナルのシグナル異常に対する抑制作用は開示されていない。特許文献4には、VEGFおよびFGFにより誘導される血管新生を抑制するピリジン誘導体またはピリミジン誘導体が開示されている。しかしながら、これらの文献には本発明に係る化合物は開示されていない。
一般に、医薬品として用いられる化合物およびその塩ならびにそれらの結晶の物性は、薬物のバイオアベイラビリティー、原薬の純度、製剤の処方などに大きな影響を与える。したがって、本発明の課題は、医薬品の原薬としての利用可能性を有する化合物(I)の塩およびその結晶を提供することにある。
[1]下記式(I)で表される5-({2-[({4-[1-(2-ヒドロキシエチル)ピペリジン-4-イル]フェニル}カルボニル)アミノ]ピリジン-4-イル}オキシ)-6-(2-メトキシエトキシ)-N-メチル-1H-インドール-1-カルボキサミドと、コハク酸またはマレイン酸からなる塩、
[3]マレイン酸からなる塩である、[1]記載の塩、
[4]5-({2-[({4-[1-(2-ヒドロキシエチル)ピペリジン-4-イル]フェニル}カルボニル)アミノ]ピリジン-4-イル}オキシ)-6-(2-メトキシエトキシ)-N-メチル-1H-インドール-1-カルボキサミド 1.5コハク酸塩である、[2]記載の塩、
[5]5-({2-[({4-[1-(2-ヒドロキシエチル)ピペリジン-4-イル]フェニル}カルボニル)アミノ]ピリジン-4-イル}オキシ)-6-(2-メトキシエトキシ)-N-メチル-1H-インドール-1-カルボキサミド 0.5コハク酸塩である、[2]記載の塩、
[6]5-({2-[({4-[1-(2-ヒドロキシエチル)ピペリジン-4-イル]フェニル}カルボニル)アミノ]ピリジン-4-イル}オキシ)-6-(2-メトキシエトキシ)-N-メチル-1H-インドール-1-カルボキサミド マレイン酸塩である、[1]記載の塩、
[7]下記式(I)で表される5-({2-[({4-[1-(2-ヒドロキシエチル)ピペリジン-4-イル]フェニル}カルボニル)アミノ]ピリジン-4-イル}オキシ)-6-(2-メトキシエトキシ)-N-メチル-1H-インドール-1-カルボキサミドと、コハク酸またはマレイン酸からなる塩の結晶、
[11]粉末X線回折において、回折角度(2θ±0.2°)22.4°、25.3°および23.3°に回折ピークを有する、[10]の結晶、
[12]粉末X線回折において、回折角度(2θ±0.2°)19.8°に回折ピークを有する、5-({2-[({4-[1-(2-ヒドロキシエチル)ピペリジン-4-イル]フェニル}カルボニル)アミノ]ピリジン-4-イル}オキシ)-6-(2-メトキシエトキシ)-N-メチル-1H-インドール-1-カルボキサミド 0.5コハク酸塩の結晶(α)、
[13]粉末X線回折において、回折角度(2θ±0.2°)20.1°に回折ピークを有する、5-({2-[({4-[1-(2-ヒドロキシエチル)ピペリジン-4-イル]フェニル}カルボニル)アミノ]ピリジン-4-イル}オキシ)-6-(2-メトキシエトキシ)-N-メチル-1H-インドール-1-カルボキサミド マレイン酸塩の結晶、
[14]13C固体NMRスペクトルにおいて、化学シフト(±0.5ppm)108.5ppm、155.1ppmおよび179.9ppmにピークを有する、5-({2-[({4-[1-(2-ヒドロキシエチル)ピペリジン-4-イル]フェニル}カルボニル)アミノ]ピリジン-4-イル}オキシ)-6-(2-メトキシエトキシ)-N-メチル-1H-インドール-1-カルボキサミド 1.5コハク酸塩の結晶、
[15]13C固体NMRスペクトルにおいて、化学シフト(±0.5ppm)27.1ppm、34.8ppm、108.5ppm、155.1ppmおよび179.9ppmにピークを有する、[14]の結晶、
[16]図1の粉末X線回折パターンを有する、5-({2-[({4-[1-(2-ヒドロキシエチル)ピペリジン-4-イル]フェニル}カルボニル)アミノ]ピリジン-4-イル}オキシ)-6-(2-メトキシエトキシ)-N-メチル-1H-インドール-1-カルボキサミド 1.5コハク酸塩の結晶、
[17] [1]~[16]のいずれか一つに記載の塩または結晶を有効成分として含有する医薬組成物。
回折角度(2θ±0.2°)22.4°に回折ピークを有する、化合物(I)・1.5コハク酸塩の結晶;
回折角度(2θ±0.2°)22.4°および25.3°に回折ピークを有する、化合物(I)・1.5コハク酸塩の結晶;
回折角度(2θ±0.2°)22.4°、25.3°および23.3°に回折ピークを有する、化合物(I)・1.5コハク酸塩の結晶;
回折角度(2θ±0.2°)22.4°、25.3°、23.3°、13.2°および22.0°に回折ピークを有する、化合物(I)・1.5コハク酸塩の結晶;
回折角度(2θ±0.2°)22.4°、25.3°、23.3°、13.2°、22.0°、19.3°、15.7°、22.7°、20.6°および16.0°に回折ピークを有する、化合物(I)・1.5コハク酸塩の結晶;
回折角度(2θ±0.2°)19.8°に回折ピークを有する、化合物(I)・0.5コハク酸塩の結晶(α);
回折角度(2θ±0.2°)19.8°および15.7°に回折ピークを有する、化合物(I)・0.5コハク酸塩の結晶(α);
回折角度(2θ±0.2°)19.8°、15.7°および13.9°に回折ピークを有する、化合物(I)・0.5コハク酸塩の結晶(α);
回折角度(2θ±0.2°)19.8°、15.7°、13.9°、21.4°および25.0°に回折ピークを有する、化合物(I)・0.5コハク酸塩の結晶(α);
回折角度(2θ±0.2°)19.8°、15.7°、13.9°、21.4°、25.0°、20.6°、18.2°、26.8°、18.8°および22.4°に回折ピークを有する、化合物(I)・0.5コハク酸塩の結晶(α);
回折角度(2θ±0.2°)16.6°に回折ピークを有する、化合物(I)・0.5コハク酸塩の結晶(β);
回折角度(2θ±0.2°)16.6°および19.7°に回折ピークを有する、化合物(I)・0.5コハク酸塩の結晶(β);
回折角度(2θ±0.2°)16.6°、19.7°および15.7°に回折ピークを有する、化合物(I)・0.5コハク酸塩の結晶(β);
回折角度(2θ±0.2°)16.6°、19.7°、15.7°、9.3°および14.3°に回折ピークを有する、化合物(I)・0.5コハク酸塩の結晶(β);
回折角度(2θ±0.2°)16.6°、19.7°、15.7°、9.3°、14.3°、21.8°、20.6°、18.7°、18.1°および26.5°に回折ピークを有する、化合物(I)・0.5コハク酸塩の結晶(β);
回折角度(2θ±0.2°)20.1°に回折ピークを有する、化合物(I)・マレイン酸塩の結晶;
回折角度(2θ±0.2°)20.1°および17.0°に回折ピークを有する、化合物(I)・マレイン酸塩の結晶;
回折角度(2θ±0.2°)20.1°、17.0°および16.2°に回折ピークを有する、化合物(I)・マレイン酸塩の結晶;
回折角度(2θ±0.2°)20.1°、17.0°、16.2°、22.8°および21.9°に回折ピークを有する、化合物(I)・マレイン酸塩の結晶;
回折角度(2θ±0.2°)20.1°、17.0°、16.2°、22.8°、21.9°、25.8°、9.0°、15.2°、24.3°および19.6°に回折ピークを有する、化合物(I)・マレイン酸塩の結晶;
13C固体NMRスペクトルにおいて、化学シフト(±0.5ppm)108.5ppm、155.1ppmおよび179.9ppmにピークを有する、化合物(I)・1.5コハク酸塩の結晶;
または、
13C固体NMRスペクトルにおいて、化学シフト(±0.5ppm)27.1ppm、34.8ppm、108.5ppm、155.1ppmおよび179.9ppmにピークを有する、化合物(I)・1.5コハク酸塩の結晶などを挙げることができる。
化合物(I)は、後述する製造例1に記載の方法で合成することができる。
本発明に係る化合物(I)の塩は、通常の塩を製造する方法により得ることができる。具体的には、例えば、化合物(I)を溶媒に、必要に応じて加温して、懸濁または溶解させ、次いで、得られる懸濁液または溶液に、酸を加え、室温下あるいは冷却しながら数分から数日間、撹拌または放置することにより、製造することができる。これらの製造方法により、化合物(I)の塩を、結晶または非晶質として得ることができる。また、非晶質は、これらの製造方法に、必要に応じて、さらに凍結乾燥等の操作を行うことにより得ることもできる。ここで使用する溶媒としては、例えばエタノール、1-プロパノール、イソプロパノール等のアルコール系溶媒;アセトニトリル;アセトン、2-ブタノン等のケトン系溶媒;酢酸エチル等のエステル系溶媒;ヘキサン、ヘプタン等の飽和炭化水素系溶媒;t-ブチルメチルエーテル等のエーテル系溶媒または水を挙げることができる。これらの溶媒は単独で使用してもよく、2種以上を混合して使用してもよい。
化合物(I)またはその塩の結晶は、上述の化合物(I)の製造方法、またはその塩の製造方法により製造することができ、または、化合物(I)またはその塩を、溶媒中で加熱溶解し、攪拌下冷却して晶析することにより、製造することもできる。
賦形剤としては、例えば、乳糖、結晶セルロース等を、結合剤としては、例えば、ヒドロキシプロピルセルロース等を、崩壊剤としては、例えば、クロスカルメロースナトリウム等を、滑沢剤としては、例えば、ステアリン酸マグネシウム等を、着色剤としては、例えば、酸化チタン等を、コーティング剤としては、例えば、ヒドロキシプロピルメチルセルロース等を挙げることができるが、これらに限定されるものではない。
これらの錠剤、カプセル剤、顆粒剤、散剤等の固形製剤は、通常、医薬品として利用できる薬効を示す限り、任意の量の化合物(I)の塩またはその結晶を含むことができる。
pH調整剤や緩衝剤としては、例えば、有機酸または無機酸および/またはその薬剤学的に許容される塩等を、懸濁化剤としては、例えば、ヒドロキシプロピルセルロース等を、溶解補助剤としては、例えば、ポリソルベート80等を、抗酸化剤としては、例えば、α-トコフェロール等を、保存剤としては、例えば、パラオキシ安息香酸メチル、パラオキシ安息香酸エチル等を、等張化剤としては、例えば、ブドウ糖等を挙げることができるが、これらに限定されるものではない。
これらの注射剤は、通常、医薬品として利用できる薬効を示す限り、任意の量の化合物(I)の塩またはその結晶を含むことができる。
使用する基剤原料としては、例えば、医薬品、医薬部外品、化粧品等に通常使用される各種原料を用いることが可能である。具体的には例えば、動植物油、鉱物油、エステル油、ワックス類、乳化剤、高級アルコール類、脂肪酸類、シリコン油、界面活性剤、リン脂質類、アルコール類、多価アルコール類、水溶性高分子類、粘土鉱物類、精製水等の原料を挙げることができる。
これらの外用剤は、通常、医薬品として利用できる薬効を示す限り、任意の量の化合物(I)の塩またはその結晶を含むことができる。
サンプルホルダー:アルミニウム
ターゲット:銅
検出器:シンチレーションカウンター
管電圧:50kV
管電流:300mA
スリット:DS 0.5 mm(Height limiting slit 2 mm),SS Open, RS Open
走査速度:10°/分
サンプリング間隔:0.02°
走査範囲:5~35°
測定条件
使用装置:AVANCE400(BRUKER社製)
測定温度:室温(22℃)
基準物質:グリシン(外部基準:176.03ppm)
測定核:13C(100.6248425MHz)
パルス繰り返し時間:3秒
パルスモード:TOSS測定
1H-NMR Spectrum (CDCl3) δ(ppm): 2.21 (3H, s), 7.05 (1H, dd, J=5.4, 1.9 Hz), 8.15 (1H, d, J=5.4 Hz), 8.30 (2H, brs).
1H-NMR Spectrum (CDCl3) δ(ppm): 2.90 (3H, d, J=4.9 Hz), 4.95 (1H, brs), 7.08-7.16 (2H, m), 7.16-7.24 (1H, m), 7.31-7.41 (2H, m).
1H-NMR Spectrum (CDCl3) δ(ppm): 1.52-1.78 (2H, m), 1.81-1.99 (2H, m), 2.14 (3H, s), 2.63 (1H, td, J=12.9, 2.7 Hz), 2.74 (1H, tt, J=12.1, 3.7 Hz), 3.17 (1H, td, J=13.2, 2.6 Hz), 3.84-4.02 (1H, m), 4.69-4.89 (1H, m), 7.08-7.43 (5H, m).
1H-NMR Spectrum (CDCl3) δ(ppm): 1.49-1.82 (2H, m), 1.92 (2H, t, J=13.2 Hz), 2. 15 (3H, s), 2.65 (1H, t, J=11.7 Hz), 2.75-2.94 (1H, m), 3.08-3.30 (1H, m), 3.97 (1H, d, J=13.2 Hz), 4.82 (1H, d, J=12.8 Hz), 7.30 (2H, d, J=8.4 Hz), 8.05 (2H, d, J=8.1 Hz).
1H-NMR Spectrum (DMSO-d6) δ(ppm): 1.60-2.15 (4H, m), 2.76-3.16 (3H, m), 3.27-3.45 (2H, m), 7.36 (2H, d, J=8.1 Hz), 7.92 (2H, d, J=8.1 Hz), 8.65-9.04 (2H, m), 12.89 (1H, brs).
1H-NMR Spectrum (CDCl3) δ(ppm): 1.49 (9H, s), 1.57-1.76 (2H, m), 1.84 (2H, d, J=13.5 Hz), 2.62-2.97 (3H, m), 4.27 (2H, brs), 7.28-7.36 (2H, m), 7.98-8.10 (2H, m).
1H-NMR Spectrum (CDCl3) δ(ppm): 3.47 (3H, s), 3.76-3.80 (2H, m), 4.25-4.29 (2H, m), 6.40 (1H, brs), 7.01 (1H, d, J=8.4 Hz), 7.41 (1H, dd, J=8.2, 2.0 Hz), 7.45 (1H, d, J=1.8 Hz), 9.85 (1H, s).
1H-NMR Spectrum (CDCl3) δ(ppm): 3.46 (3H, s), 3.79-3.85 (2H, m), 4.24-4.30 (2H, m), 5.18 (2H, s), 7.03 (1H, d, J=8.1 Hz), 7.29-7.35 (1H, m), 7.35-7.41 (2H, m), 7.43-7.50 (4H, m), 9.82 (1H, s).
1H-NMR Spectrum (CDCl3) δ(ppm): 3.46 (3H, s), 3.78-3.84 (2H, m), 4.21-4.27 (2H, m), 5.16 (2H, s), 6.97 (1H, d, J=8.4 Hz), 7.06 (1H, d, J=1.8 Hz), 7.16 (1H, dd, J=8.4, 2.2 Hz), 7.30-7.48 (6H, m), 7.91 (1H, d, J=13.5 Hz).
粗生成物(23.0g)をメタノール(500mL)に懸濁させた後、室温で10%パラジウム-炭素(50%含水品)(8g)を加えて水素雰囲気下で6時間攪拌した。触媒をセライトを用いて濾過後、濾液を減圧濃縮し、シリカゲルカラムクロマトグラフィー(n-ヘプタン:酢酸エチル=2:1~1:1)で精製した。目的物画分を減圧濃縮し、標記化合物(3.94g、31%)を得た。
1H-NMR Spectrum (CDCl3) δ(ppm): 3.48 (3H, s), 3.69-3.78 (2H, m), 4.16-4.23 (2H, m), 6.24 (1H, s), 6.41 (1H, ddd, J=3.1, 2.1, 0.8 Hz), 6.97 (1H, s), 7.10 (1H, dd, J=3.2, 2.5 Hz), 7.15 (1H, s), 7.94 (1H, brs).
1H-NMR Spectrum (500MHz, CDCl3) δ(ppm): 2.13 (3H, s), 3.27 (3H, s), 3.54-3.58 (2H, m), 4.07-4.11 (2H, m), 6.46-6.50 (1H, m), 6.54 (1H, dd, J=5.8, 1.9 Hz), 7.05 (1H, s), 7.14-7.17 (1H, m), 7.36 (1H, s), 7.75 (1H, brs), 8.02 (1H, d, J=5.8 Hz), 8.10 (1H, brs), 8.19 (1H, brs).
1H-NMR Spectrum (500MHz, CDCl3) δ(ppm): 3.31 (3H, s), 3.58-3.63 (2H, m), 4.08-4.11 (2H, m), 4.28 (2H, brs), 5.90 (1H, d, J=2.4 Hz), 6.29 (1H, dd, J=6.1, 2.2 Hz), 6.44-6.52 (1H, m), 7.06 (1H, s), 7.15-7.20 (1H, m), 7.34 (1H, s), 7.88 (1H, d, J=5.8 Hz), 8.22 (1H, brs).
1H-NMR Spectrum (500MHz, CDCl3) δ(ppm): 3.06 (3H, d, J=4.9 Hz), 3.29 (3H, s), 3.59-3.63 (2H, m), 4.14-4.17 (2H, m), 4.30 (2H, brs), 5.52-5.59 (1H, m), 5.89 (1H, d, J=2.4 Hz), 6.27 (1H, dd, J=5.8, 1.9 Hz), 6.55 (1H, d, J=3.9 Hz), 7.27-7.29 (2H, m), 7.89 (1H, d, J=5.9 Hz), 7.99 (1H, s).
粗生成物(1.11g)をジクロロメタン(50mL)に溶解させ、室温でトリフルオロ酢酸(5.0mL)を加えた。室温にて30分間攪拌後、減圧濃縮し、残渣をジクロロメタンとトリエチルアミンに溶解させ、減圧濃縮した。残渣をNHシリカゲルカラムクロマトグラフィー(酢酸エチル:メタノール=1:0~22:3)で精製し、標記化合物(829mg、57%)を得た。
1H-NMR Spectrum (500MHz, CDCl3) δ(ppm): 1.59-1.69 (2H, m), 1.83 (2H, d, J=14.1 Hz), 2.68 (1H, tt, J=12.0, 3.6 Hz), 2.75 (2H, td, J=12.2, 2.4 Hz), 3.04 (3H, d, J=4.9 Hz), 3.17-3.23 (2H, m), 3.26 (3H, s), 3.55-3.61 (2H, m), 4.15-4.21 (2H, m), 5.57-5.65 (1H, m), 6.53 (1H, d, J=3.4 Hz), 6.62 (1H, dd, J=5.8, 2.4 Hz), 7.25 (1H, d, J=3.9 Hz), 7.30-7.34 (3H, m), 7.77-7.82 (2H, m), 7.91 (1H, d, J=2.4 Hz), 8.02 (1H, s), 8.10 (1H, d, J=5.9 Hz), 8.50 (1H, brs).
1H-NMR Spectrum (CDCl3) δ(ppm): 1.70-1.92 (4H, m), 2.15-2.24 (2H, m), 2.53-2.65 (3H, m), 3.01-3.09 (5H, m), 3.26 (3H, s), 3.56-3.60 (2H, m), 3.64 (2H, t, J=5.2 Hz), 4.15-4.20 (2H, m), 5.49-5.54 (1H, m), 6.55 (1H, d, J=3.7 Hz), 6.61 (1H, dd, J=5.8, 2.3 Hz), 7.24-7.28 (1H, m), 7.30-7.35 (3H, m), 7.81 (2H, d, J=8.2 Hz), 7.91 (1H, d, J=2.4 Hz), 8.01 (1H, s), 8.10 (1H, d, J=5.9 Hz), 8.50 (1H, brs).
1H-NMR Spectrum (600MHz, CD3OD) δ(ppm): 1.96-2.10 (4H, m), 2.52 (6H, s), 2.93 (1H, m), 2.96 (3H, s), 3.01 (2H, m), 3.16 (2H, t, J=5.4 Hz), 3.22 (3H, s), 3.56 (2H, t, J=4.7 Hz), 3.61 (2H, m), 3.87 (2H, t, J=5.4 Hz), 4.14 (2H, t, J=4.6 Hz), 6.61 (1H, d, J=3.6 Hz), 6.68 (1H, dd, J=5.8, 2.3 Hz), 7.37 (1H, s), 7.42 (2H, d, J=8.3 Hz), 7.58 (1H, d, J=3.6 Hz), 7.73 (1H, d, J=2.2 Hz), 7.88 (2H, d, J=8.3 Hz), 8.08 (1H, s), 8.15 (1H, d, J=5.8 Hz).
13C-NMR(100MHz,solid state) δ(ppm): 27.1, 28.3, 29.7, 34.8, 38.0, 41.3, 54.0, 57.3, 59.7, 60.9, 72.1, 72.5, 103.3, 104.2, 108.5, 116.9, 126.9, 128.6, 134.5, 136.7, 140.7, 149.4, 151.3, 155.1, 169.5, 170.1, 175.6, 179.9, 183.7.
1H-NMR Spectrum (600MHz, CD3OD) δ(ppm): 1.86-2.00 (4H, m), 2.51 (2H, s), 2.62 (2H, m), 2.79 (1H, m), 2.87 (2H, t, J=5.5 Hz), 2.96 (3H, s), 3.22 (3H, s), 3.36 (2H, d, J=11.8 Hz), 3.56 (2H, t, J=4.6 Hz), 3.79 (2H, t, J=5.7 Hz), 4.15 (2H, t, J=4.6 Hz), 6.61 (1H, d, J=3.6 Hz), 6.68 (1H, dd, J=5.7, 2.1 Hz), 7.37 (1H, s), 7.40 (2H, d, J=8.2 Hz), 7.58 (1H, d, J=3.6 Hz), 7.73 (1H, d, J=2.0 Hz), 7.86 (2H, d, J=8.3 Hz), 8.08 (1H, s), 8.14 (1H, d, J=5.8 Hz).
1H-NMR Spectrum (CD3OD) δ(ppm): 1.86-2.00 (4H, m), 2.51 (2H, s), 2.62 (2H, m), 2.79 (1H, m), 2.87 (2H, brt, J=5.5 Hz), 2.96 (3H, s), 3.22 (3H, s), 3.36 (2H, brd, J=11.8 Hz), 3.56 (2H, brt, J=4.6 Hz), 3.79 (2H, t, J=5.7 Hz), 4.15 (2H, brt, J=4.6 Hz), 6.61 (1H, d, J=3.6 Hz), 6.68 (1H, dd, J=5.7, 2.1 Hz), 7.37 (1H, s), 7.40 (2H, d, J=8.2 Hz), 7.58 (1H, d, J=3.6 Hz), 7.73 (1H, d, J=2.0 Hz), 7.86 (2H, d, J=8.3 Hz), 8.08 (1H, s), 8.14 (1H, d, J=5.8 Hz)
1H-NMR Spectrum (CD3OD) δ(ppm): 1.87-2.00 (4H, m), 2.51 (2H, s), 2.65 (2H, m), 2.79 (1H, m), 2.89 (2H, brt, J=5.6 Hz), 2.95 (3H, s), 3.22 (3H, s), 3.38 (2H, brd, J=12.1 Hz), 3.56 (2H, m), 3.80 (2H, t, J=5.6 Hz), 4.14 (2H, m), 6.60 (1H, d, J=3.7 Hz), 6.67 (1H, dd, J=5.8, 2.3 Hz), 7.37 (1H, s), 7.40 (2H, d, J=8.4 Hz), 7.57 (1H, d, J=3.7 Hz), 7.73 (1H, d, J=2.3 Hz), 7.86 (2H, d, J=8.4 Hz), 8.08 (1H, s), 8.14 (1H, d, J=5.8 Hz)
1H-NMR Spectrum (CD3OD) δ(ppm): 1.96-2.11 (4H, m), 2.53 (6H, s), 2.93 (1H, m), 2.96 (3H, s), 3.00 (2H, m), 3.15 (2H, t, J=5.4 Hz), 3.22 (3H, s), 3.56 (2H, m), 3.60 (2H, brd, J=12.4 Hz), 3.87 (2H, t, J=5.5 Hz), 4.15 (2H, brt, J=4.6 Hz), 6.61 (1H, d, J=3.7 Hz), 6.68 (1H, brd, J=3.8 Hz), 7.37 (1H, s), 7.42 (2H, d, J=8.3 Hz), 7.58 (1H, d, J=3.8 Hz), 7.73 (1H, brs), 7.88 (2H, d, J=8.3 Hz), 8.08 (1H, s), 8.15 (1H, brd, J=5.0 Hz)
以下の試験例を行い、製造例1-15記載の化合物(I)もしくは化合物(I)の塩またはその結晶の、物性または薬理効果を調べた。
動的水分吸着測定装置により、実施例1の化合物(I)・1.5コハク酸塩の吸湿性を評価した。装置の試料装着部位を25℃に保温し、相対湿度(RH)を5%~95%の範囲で段階的に設定した。湿度は0%RHの乾燥窒素および100%RHの加湿窒素の相対流量を変えることで調節した。試料重量は2分間隔ごとにミクロ天秤で確認され、5分間の重量変動幅が0.01%を下回った時点で順次湿度を変更した。その結果を図5に示す。
平底96ウェル白プレート(住友ベークライト MS-8496W)に、アッセイバッファー(20mM HEPES-NaOH、0.01% TritonX-100、2mM DTT、5mM MgCl2)にて1μg/mLに希釈したFGFR1蛋白(カルナバイオサイエンス社 08-133)溶液10μl、最終濃度1000nMのCSK-tide substrate(AnaSpec Inc 63843)および最終濃度58.3μMのATP(promega V9102)を含むアッセイバッファー溶液10μL、アッセイバッファーにて希釈した被験物質5μlを加え、室温で1時間反応させた。キナーゼ活性測定にはADP-GloTM Kinase Assay(promega V9102)を用いた。反応後のプレートにADP-Glo reagentを各ウェル25μL添加し、室温で40分間反応させキナーゼ反応を停止し、残存ATPを枯渇させた。さらにKinase detection reagentを加え、室温で40分間反応させADPからATPへの変換とルシフェラーゼ/ルシフェリンカップリング反応とATPによる発光反応を行った。EnvisionTM(パーキンエルマー株式会社)にて各ウェルの発光量を測定し酵素活性を評価した。被験物質を添加せずにキナーゼタンパク質を添加した場合の発光量を100%、被験物質およびキナーゼタンパク質を添加していない場合の発光量を0%として、被験物質存在下での発光量率を求めた。この発光量率によりキナーゼ活性を50%阻害するのに必要な被験物質の濃度(IC50値)を算出した。
ヒト胃がん細胞株SNU-16(ATCC Number CRL-5974)はFGFR2遺伝子増幅を有することが報告されている(Cancer Res.2008.68:2340-2348)。SNU-16細胞は10% FBS、ペニシリン/ストレプトマイシン(WAKO 168-23191)を含むRPMI-1640(WAKO 187-02021)培地を用い、5%CO2インキュベーター中(37℃)で培養維持を行った。96ウェルプレート(ベクトンディッキンソン 35-3075)の各ウェルに、10%FBSを含むRPMI-1640培地を用いて1×104 cells/mLに調製したSNU-16の細胞懸濁液を150μLずつ加え、5%CO2インキュベーター中(37℃)で一晩培養した。翌日、10%FBSを含むRPMI-1640培地にて希釈した被験物質を50μLずつ添加し、5%CO2インキュベーター中(37℃)で3日間培養した。Cell Counting Kit-8(同仁化学研究所 CK04)10μLを各ウェルに添加し、5%CO2インキュベーター中(37℃)で1-2時間培養し発色させた。ENVISIONTM(パーキンエルマー社)により450nmの吸光度を測定した。被験物質を添加していない場合の吸光度を100%、細胞が存在していないウェルの吸光度を0%として、被験物質存在下での吸光度率を求めた。細胞増殖を50%阻害するのに必要な被験物質の濃度(IC50値)を求め、表2に示した。
10%FBS、ペニシリン/ストレプトマイシンを含むRPMI-1640培養液で培養したヒト胃がん細胞株SNU-16をHanks’ Balanced Salt Solution (GIBCO #24020)にて1×108 cells/mL濃度に調製し、MATRIGEL(BDバイオサイエンス Cat# 354234)と1:1で混合し5×107 cells/mlの細胞懸濁液を調製した。6~7週齢のヌードマウス(BALB/cAJcl-nu/nu、雌、日本クレア株式会社)の右脇腹皮下部に100μLの容量で移植した。移植から7日後に電子デジタルノギス(デジマチックTMキャリパ、株式会社ミツトヨ)を用いて腫瘍の短径、長径を計測し、以下の計算式で腫瘍体積を算出した。
腫瘍体積(mm3)=長径(mm)×短径(mm)×短径(mm)/2
投与初日の腫瘍体積をもとに腫瘍体積の平均値がほぼ等しくなるように群分けを行った。被験物質はDMSOに溶解し、Tween80を加え、10倍濃度の溶液を調製し冷凍保存した。投与直前に5%グルコース溶液を添加し、最終投与溶液とした(DMSO:Tween80:5% glucose溶液=3.5%:6.5%:90%)。評価検体は20mL/kgの投与容量で1日1回11日間連続経口投与し、コントロール群には投与溶媒を同条件で経口投与した。尚、実験は1群5匹で行った。
コントロール群、被験物質投与群それぞれに対し、初日の体重に対する最終日の体重比(relative body weight: RBW)を算出する。被験物質投与群のRBW/コントロール群のRBWが0.9の以上の被験物質投与群を安全に投与可能な群と判定した。これに該当する被験物質投与群について、最終日におけるコントロールの腫瘍体積に対する被験物質投与後の腫瘍体積の割合(T/C)(%)を算出し、表3に示した。
Claims (15)
- コハク酸塩である、請求項1記載の塩。
- 5-({2-[({4-[1-(2-ヒドロキシエチル)ピペリジン-4-イル]フェニル}カルボニル)アミノ]ピリジン-4-イル}オキシ)-6-(2-メトキシエトキシ)-N-メチル-1H-インドール-1-カルボキサミド 1.5コハク酸塩である、請求項2記載の塩。
- 5-({2-[({4-[1-(2-ヒドロキシエチル)ピペリジン-4-イル]フェニル}カルボニル)アミノ]ピリジン-4-イル}オキシ)-6-(2-メトキシエトキシ)-N-メチル-1H-インドール-1-カルボキサミド 0.5コハク酸塩である、請求項2記載の塩。
- 5-({2-[({4-[1-(2-ヒドロキシエチル)ピペリジン-4-イル]フェニル}カルボニル)アミノ]ピリジン-4-イル}オキシ)-6-(2-メトキシエトキシ)-N-メチル-1H-インドール-1-カルボキサミド マレイン酸塩である、請求項1記載の塩。
- 粉末X線回折において、回折角度(2θ±0.2°)22.4°に回折ピークを有する、5-({2-[({4-[1-(2-ヒドロキシエチル)ピペリジン-4-イル]フェニル}カルボニル)アミノ]ピリジン-4-イル}オキシ)-6-(2-メトキシエトキシ)-N-メチル-1H-インドール-1-カルボキサミド 1.5コハク酸塩の結晶。
- 粉末X線回折において、回折角度(2θ±0.2°)22.4°、25.3°および23.3°に回折ピークを有する、請求項8記載の結晶。
- 粉末X線回折において、回折角度(2θ±0.2°)19.8°に回折ピークを有する、5-({2-[({4-[1-(2-ヒドロキシエチル)ピペリジン-4-イル]フェニル}カルボニル)アミノ]ピリジン-4-イル}オキシ)-6-(2-メトキシエトキシ)-N-メチル-1H-インドール-1-カルボキサミド 0.5コハク酸塩の結晶(α)。
- 粉末X線回折において、回折角度(2θ±0.2°)20.1°に回折ピークを有する、5-({2-[({4-[1-(2-ヒドロキシエチル)ピペリジン-4-イル]フェニル}カルボニル)アミノ]ピリジン-4-イル}オキシ)-6-(2-メトキシエトキシ)-N-メチル-1H-インドール-1-カルボキサミド マレイン酸塩の結晶。
- 13C固体NMRスペクトルにおいて、化学シフト(±0.5ppm)108.5ppm、155.1ppmおよび179.9ppmにピークを有する、5-({2-[({4-[1-(2-ヒドロキシエチル)ピペリジン-4-イル]フェニル}カルボニル)アミノ]ピリジン-4-イル}オキシ)-6-(2-メトキシエトキシ)-N-メチル-1H-インドール-1-カルボキサミド 1.5コハク酸塩の結晶。
- 13C固体NMRスペクトルにおいて、化学シフト(±0.5ppm)27.1ppm、34.8ppm、108.5ppm、155.1ppmおよび179.9ppmにピークを有する、請求項12記載の結晶。
- 図1の粉末X線回折パターンを有する、5-({2-[({4-[1-(2-ヒドロキシエチル)ピペリジン-4-イル]フェニル}カルボニル)アミノ]ピリジン-4-イル}オキシ)-6-(2-メトキシエトキシ)-N-メチル-1H-インドール-1-カルボキサミド 1.5コハク酸塩の結晶。
- 請求項1~14のいずれか一項に記載の塩または結晶を有効成分として含有する医薬組成物。
Priority Applications (13)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201580042132.3A CN106660997B (zh) | 2014-08-18 | 2015-08-17 | 单环吡啶衍生物的盐及其晶体 |
US15/500,429 US9951047B2 (en) | 2014-08-18 | 2015-08-17 | Salt of monocyclic pyridine derivative and crystal thereof |
CA2956270A CA2956270C (en) | 2014-08-18 | 2015-08-17 | Salt of monocyclic pyridine derivative and crystal thereof |
ES15834302T ES2914072T3 (es) | 2014-08-18 | 2015-08-17 | Sal de derivado de piridina monocíclico y su cristal |
JP2015560425A JP5925978B1 (ja) | 2014-08-18 | 2015-08-17 | 単環ピリジン誘導体の塩およびその結晶 |
BR112017002268-0A BR112017002268B1 (pt) | 2014-08-18 | 2015-08-17 | Sal de derivado de piridina monocíclica e cristal do mesmo |
EP15834302.0A EP3184520B1 (en) | 2014-08-18 | 2015-08-17 | Salt of monocyclic pyridine derivative and crystal thereof |
AU2015304465A AU2015304465B2 (en) | 2014-08-18 | 2015-08-17 | Salt of monocyclic pyridine derivative and crystal thereof |
SG11201700703XA SG11201700703XA (en) | 2014-08-18 | 2015-08-17 | Salt of monocyclic pyridine derivative and crystal thereof |
RU2017103439A RU2658821C1 (ru) | 2014-08-18 | 2015-08-17 | Соль моноциклического производного пиридина и ее кристалл |
KR1020177002791A KR102344105B1 (ko) | 2014-08-18 | 2015-08-17 | 모노시클릭 피리딘 유도체의 염 및 이의 결정 |
MX2017001624A MX369646B (es) | 2014-08-18 | 2015-08-17 | Sal de derivado de piridina monociclico y su cristal. |
IL250290A IL250290B (en) | 2014-08-18 | 2017-01-25 | A salt of a monocyclic pyridine derivative and its crystalline form |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2014166118 | 2014-08-18 | ||
JP2014-166118 | 2014-08-18 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2016027781A1 true WO2016027781A1 (ja) | 2016-02-25 |
Family
ID=55350725
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/JP2015/073047 WO2016027781A1 (ja) | 2014-08-18 | 2015-08-17 | 単環ピリジン誘導体の塩およびその結晶 |
Country Status (14)
Country | Link |
---|---|
US (1) | US9951047B2 (ja) |
EP (1) | EP3184520B1 (ja) |
JP (1) | JP5925978B1 (ja) |
KR (1) | KR102344105B1 (ja) |
CN (1) | CN106660997B (ja) |
AU (1) | AU2015304465B2 (ja) |
BR (1) | BR112017002268B1 (ja) |
CA (1) | CA2956270C (ja) |
ES (1) | ES2914072T3 (ja) |
IL (1) | IL250290B (ja) |
MX (1) | MX369646B (ja) |
RU (1) | RU2658821C1 (ja) |
SG (1) | SG11201700703XA (ja) |
WO (1) | WO2016027781A1 (ja) |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPWO2019189241A1 (ja) * | 2018-03-28 | 2021-03-18 | エーザイ・アール・アンド・ディー・マネジメント株式会社 | 肝細胞癌治療剤 |
AU2016374441B2 (en) * | 2015-12-17 | 2021-10-21 | Eisai R&D Management Co., Ltd. | Therapeutic agent for breast cancer |
WO2023032873A1 (ja) | 2021-08-31 | 2023-03-09 | エーザイ・アール・アンド・ディー・マネジメント株式会社 | 単環ピリジン誘導体の製造方法 |
WO2023032872A1 (ja) | 2021-08-31 | 2023-03-09 | エーザイ・アール・アンド・ディー・マネジメント株式会社 | 単環ピリジン誘導体の合成中間体の製造方法 |
Families Citing this family (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
MX2020002083A (es) * | 2017-10-12 | 2020-03-24 | Eisai R&D Man Co Ltd | Composicion farmaceutica que comprende un inhibidor tirosina cinasa selectivo para receptores del factor de crecimiento de fibroblastos (fgfr). |
CA3180128A1 (en) | 2020-04-17 | 2021-10-21 | Eisai R&D Management Co., Ltd. | Breast cancer therapeutic agent |
CA3185174A1 (en) | 2020-07-31 | 2022-02-03 | Eisai R&D Management Co., Ltd. | Therapeutic agent for breast cancer |
US20230330081A1 (en) | 2020-10-28 | 2023-10-19 | Eisai R&D Management Co., Ltd. | Pharmaceutical composition for treating tumors |
CN116768856A (zh) * | 2022-03-18 | 2023-09-19 | 上海润石医药科技有限公司 | 一种取代的氨基六元氮杂环类化合物的盐及其晶型、制备方法和应用 |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2004020434A1 (ja) * | 2002-08-30 | 2004-03-11 | Eisai Co., Ltd. | 含窒素芳香環誘導体 |
JP2009215313A (ja) * | 2000-10-20 | 2009-09-24 | Eisai R & D Management Co Ltd | 含窒素芳香環誘導体 |
WO2013010380A1 (en) * | 2011-07-19 | 2013-01-24 | Merck Sharp & Dohme Corp. | Btk inhibitors |
JP5600229B1 (ja) * | 2013-02-20 | 2014-10-01 | エーザイ・アール・アンド・ディー・マネジメント株式会社 | 単環ピリジン誘導体 |
Family Cites Families (56)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE10006139A1 (de) | 2000-02-11 | 2001-08-16 | Merck Patent Gmbh | Indol-3-yl-Derivate |
US20030187026A1 (en) | 2001-12-13 | 2003-10-02 | Qun Li | Kinase inhibitors |
US7098332B2 (en) | 2002-12-20 | 2006-08-29 | Hoffmann-La Roche Inc. | 5,8-Dihydro-6H-pyrido[2,3-d]pyrimidin-7-ones |
MXPA05010765A (es) | 2003-04-10 | 2005-12-12 | Hoffmann La Roche | Compuestos pirimido. |
US20050256154A1 (en) | 2004-05-04 | 2005-11-17 | Kin-Chun Luk | 4-Amino-thieno[3,2-c]pyridine-7-carboxylic acid amides |
GB0512324D0 (en) | 2005-06-16 | 2005-07-27 | Novartis Ag | Organic compounds |
FR2883286B1 (fr) | 2005-03-16 | 2008-10-03 | Sanofi Aventis Sa | NOUVEAUX DERIVES D'IMIDAZO[1,5-a]PYRIDINES, INHIBITEURS DE FGFs, LEUR PROCEDE DE PREPARATION ET LES COMPOSITIONS PHARMACEUTIQUES LES CONTENANT |
BRPI0611375A2 (pt) | 2005-05-23 | 2010-08-31 | Novartis Ag | formas cristalinas e outras de sais de ácido láctico de 4-amino-5-flúor-3-[6-(4-metilpiperazin-1-il)-1h-benzimid azol-2-il]-1h-quinolin-2-ona |
CA2634047C (en) | 2005-12-21 | 2016-04-12 | Novartis Ag | Pyrimidinyl aryl urea derivatives being fgf inhibitors |
TW200811134A (en) | 2006-07-12 | 2008-03-01 | Irm Llc | Compounds and compositions as protein kinase inhibitors |
EP1891955A1 (en) | 2006-07-24 | 2008-02-27 | Sanofi-Aventis | Use of 1,2,3-substituted indolizine derivatives, inhibitors of FGFs, for the preparation of a medicament intended for the treatment of degenerative joint diseases |
US7737149B2 (en) | 2006-12-21 | 2010-06-15 | Astrazeneca Ab | N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-4-(3,5-dimethylpiperazin-1-yl)benzamide and salts thereof |
JP5442449B2 (ja) | 2006-12-22 | 2014-03-12 | アステックス、セラピューティックス、リミテッド | 新規化合物 |
US8131527B1 (en) | 2006-12-22 | 2012-03-06 | Astex Therapeutics Ltd. | FGFR pharmacophore compounds |
AR064491A1 (es) | 2006-12-22 | 2009-04-08 | Astex Therapeutics Ltd | Derivados de imidazo[1, 2-a]pirimidina, un proceso para su preparacion, una composicion farmaceutica que los comprende y su uso en el tratamiento de enfermedades mediadas por las quinasas fgfr. |
CA2690355A1 (en) | 2007-06-25 | 2008-12-31 | Qinetiq Limited | Preconcentrator device incorporating a polymer of intrinsic microporosity |
WO2009019518A1 (en) | 2007-08-09 | 2009-02-12 | Astrazeneca Ab | Pyrimidine compounds having a fgfr inhibitory effect |
GB0720038D0 (en) | 2007-10-12 | 2007-11-21 | Astex Therapeutics Ltd | New compounds |
GB0720041D0 (en) | 2007-10-12 | 2007-11-21 | Astex Therapeutics Ltd | New Compounds |
WO2009056886A1 (en) | 2007-11-01 | 2009-05-07 | Astrazeneca Ab | Pyrimidine derivatives and their use as modulators of fgfr activity |
CL2008003675A1 (es) | 2007-12-13 | 2009-03-20 | Wyeth Corp | Compuestos derivados de 5-alquil o alquenil 3-cianopiridinas, procedimiento de preparacion, composicion farmaceutica, util para reducir la actividad incrementada de una enzima en un mamifero, en donde dicha enzima es una proteina quinasa, destinado al tratamiento de la inflamacion, asma, colitis, esclerosis multiple, soriasis, artritis reumatoide. |
AU2009248774B2 (en) | 2008-05-23 | 2012-05-31 | Novartis Ag | Derivatives of quinolines and quinoxalines as protein tyrosine kinase inhibitors |
GB0810902D0 (en) | 2008-06-13 | 2008-07-23 | Astex Therapeutics Ltd | New compounds |
JP2011524888A (ja) | 2008-06-19 | 2011-09-08 | アストラゼネカ アクチボラグ | ピラゾール化合物436 |
CA2748276A1 (en) | 2008-12-30 | 2010-07-08 | Arqule, Inc. | Substituted pyrazolo [3, 4-b] pyridine compounds |
CA2748174A1 (en) | 2008-12-30 | 2010-07-08 | Arqule, Inc. | Substituted 1h-pyrazolo[3,4-d]pyrimidine-6-amine compounds |
US8357694B2 (en) | 2008-12-30 | 2013-01-22 | Arqule, Inc. | Substituted 5,6-dihydro-6-phenylbenzo[F]isoquinolin-2-amine compounds |
US9002427B2 (en) | 2009-03-30 | 2015-04-07 | Lifewave Biomedical, Inc. | Apparatus and method for continuous noninvasive measurement of respiratory function and events |
GB0906472D0 (en) | 2009-04-15 | 2009-05-20 | Astex Therapeutics Ltd | New compounds |
GB0906470D0 (en) | 2009-04-15 | 2009-05-20 | Astex Therapeutics Ltd | New compounds |
FR2947546B1 (fr) | 2009-07-03 | 2011-07-01 | Sanofi Aventis | Derives de pyrazoles, leur preparation et leur application en therapeutique |
EP2270043A1 (en) | 2009-07-03 | 2011-01-05 | Sanofi-Aventis | Extracellular allosteric inhibitor binding domain from a tyrosine kinase receptor |
CN102574836B (zh) | 2009-08-07 | 2014-04-16 | 中外制药株式会社 | 氨基吡唑衍生物 |
US20120220600A1 (en) | 2009-10-30 | 2012-08-30 | Reiner Aichholz | N-Oxide of 3-(2,6-dichloro-3,5-dimethoxy-phenyl) -1--1-methyl-urea |
AR079257A1 (es) | 2009-12-07 | 2012-01-04 | Novartis Ag | Formas cristalinas de 3-(2,6-dicloro-3-5-dimetoxi-fenil)-1-{6-[4-(4-etil-piperazin-1-il)-fenil-amino]-pirimidin-4-il}-1-metil-urea y sales de las mismas |
GB201007286D0 (en) | 2010-04-30 | 2010-06-16 | Astex Therapeutics Ltd | New compounds |
FR2962437B1 (fr) | 2010-07-06 | 2012-08-17 | Sanofi Aventis | Derives d'imidazopyridine, leur procede de preparation et leur application en therapeutique |
GB201020179D0 (en) | 2010-11-29 | 2011-01-12 | Astex Therapeutics Ltd | New compounds |
US8754114B2 (en) | 2010-12-22 | 2014-06-17 | Incyte Corporation | Substituted imidazopyridazines and benzimidazoles as inhibitors of FGFR3 |
HUE041987T2 (hu) | 2011-07-19 | 2019-06-28 | Merck Sharp & Dohme | 4-Imidazopiridazin-1-il-benzamidok és 4-imidazotriazin-1-il-benzamidok mint BTK-gátlók |
GB201118654D0 (en) | 2011-10-28 | 2011-12-07 | Astex Therapeutics Ltd | New compounds |
GB201118652D0 (en) | 2011-10-28 | 2011-12-07 | Astex Therapeutics Ltd | New compounds |
GB201118656D0 (en) | 2011-10-28 | 2011-12-07 | Astex Therapeutics Ltd | New compounds |
GB201118675D0 (en) | 2011-10-28 | 2011-12-14 | Astex Therapeutics Ltd | New compounds |
FR2984325A1 (fr) | 2011-12-14 | 2013-06-21 | Sanofi Sa | Derives de pyrazolopyridine, leur procede de preparation et leur application en therapeutique |
KR101623286B1 (ko) | 2012-01-19 | 2016-05-20 | 다이호야쿠힌고교 가부시키가이샤 | 3,5-이치환 벤젠알키닐 화합물 및 그의 염 |
JP5343177B1 (ja) | 2012-02-28 | 2013-11-13 | アステラス製薬株式会社 | 含窒素芳香族へテロ環化合物 |
GB201209609D0 (en) | 2012-05-30 | 2012-07-11 | Astex Therapeutics Ltd | New compounds |
ME03300B (me) | 2012-06-13 | 2019-07-20 | Incyte Holdings Corp | Supsтituisana triciklična jedinjenja као inhibiтori fgfr |
US20150191791A1 (en) | 2012-07-05 | 2015-07-09 | Lsip, Llc | Fgfr2 fusion gene |
SG11201500125QA (en) | 2012-07-11 | 2015-02-27 | Blueprint Medicines Corp | Inhibitors of the fibroblast growth factor receptor |
US9388185B2 (en) | 2012-08-10 | 2016-07-12 | Incyte Holdings Corporation | Substituted pyrrolo[2,3-b]pyrazines as FGFR inhibitors |
WO2014044846A1 (en) | 2012-09-24 | 2014-03-27 | Evotec (Uk) Ltd. | 3-(aryl- or heteroaryl-amino)-7-(3,5-dimethoxyphenyl)isoquinoline derivatives as fgfr inhibitors useful for the treatment of proliferative disorders or dysplasia |
WO2014048878A1 (en) | 2012-09-26 | 2014-04-03 | Evotec (Uk) Ltd. | Phenyl- or pyridyl- pyrrolo[2,3b]pyrazine derivatives useful in the treatment or prevention of proliferative disorders or dysplasia |
EP2902489B9 (en) | 2012-09-27 | 2018-02-07 | Chugai Seiyaku Kabushiki Kaisha | Fgfr3 fusion gene and pharmaceutical drug targeting same |
TWI628176B (zh) | 2013-04-04 | 2018-07-01 | 奧利安公司 | 蛋白質激酶抑制劑 |
-
2015
- 2015-08-17 CN CN201580042132.3A patent/CN106660997B/zh active Active
- 2015-08-17 JP JP2015560425A patent/JP5925978B1/ja active Active
- 2015-08-17 US US15/500,429 patent/US9951047B2/en active Active
- 2015-08-17 RU RU2017103439A patent/RU2658821C1/ru active
- 2015-08-17 CA CA2956270A patent/CA2956270C/en active Active
- 2015-08-17 ES ES15834302T patent/ES2914072T3/es active Active
- 2015-08-17 SG SG11201700703XA patent/SG11201700703XA/en unknown
- 2015-08-17 MX MX2017001624A patent/MX369646B/es active IP Right Grant
- 2015-08-17 EP EP15834302.0A patent/EP3184520B1/en active Active
- 2015-08-17 AU AU2015304465A patent/AU2015304465B2/en active Active
- 2015-08-17 KR KR1020177002791A patent/KR102344105B1/ko active IP Right Grant
- 2015-08-17 WO PCT/JP2015/073047 patent/WO2016027781A1/ja active Application Filing
- 2015-08-17 BR BR112017002268-0A patent/BR112017002268B1/pt active IP Right Grant
-
2017
- 2017-01-25 IL IL250290A patent/IL250290B/en active IP Right Grant
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2009215313A (ja) * | 2000-10-20 | 2009-09-24 | Eisai R & D Management Co Ltd | 含窒素芳香環誘導体 |
WO2004020434A1 (ja) * | 2002-08-30 | 2004-03-11 | Eisai Co., Ltd. | 含窒素芳香環誘導体 |
WO2013010380A1 (en) * | 2011-07-19 | 2013-01-24 | Merck Sharp & Dohme Corp. | Btk inhibitors |
JP5600229B1 (ja) * | 2013-02-20 | 2014-10-01 | エーザイ・アール・アンド・ディー・マネジメント株式会社 | 単環ピリジン誘導体 |
Non-Patent Citations (1)
Title |
---|
See also references of EP3184520A4 * |
Cited By (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AU2016374441B2 (en) * | 2015-12-17 | 2021-10-21 | Eisai R&D Management Co., Ltd. | Therapeutic agent for breast cancer |
JPWO2019189241A1 (ja) * | 2018-03-28 | 2021-03-18 | エーザイ・アール・アンド・ディー・マネジメント株式会社 | 肝細胞癌治療剤 |
US11219619B2 (en) | 2018-03-28 | 2022-01-11 | Eisai R&D Management Co., Ltd. | Therapeutic agent for hepatocellular carcinoma |
WO2023032873A1 (ja) | 2021-08-31 | 2023-03-09 | エーザイ・アール・アンド・ディー・マネジメント株式会社 | 単環ピリジン誘導体の製造方法 |
WO2023032872A1 (ja) | 2021-08-31 | 2023-03-09 | エーザイ・アール・アンド・ディー・マネジメント株式会社 | 単環ピリジン誘導体の合成中間体の製造方法 |
JP7315806B1 (ja) | 2021-08-31 | 2023-07-26 | エーザイ・アール・アンド・ディー・マネジメント株式会社 | 単環ピリジン誘導体の製造方法 |
JP7315805B1 (ja) | 2021-08-31 | 2023-07-26 | エーザイ・アール・アンド・ディー・マネジメント株式会社 | 単環ピリジン誘導体の合成中間体の製造方法 |
KR20240052933A (ko) | 2021-08-31 | 2024-04-23 | 에자이 알앤드디 매니지먼트 가부시키가이샤 | 모노사이클릭 피리딘 유도체를 제조하기 위한 방법 |
KR20240052932A (ko) | 2021-08-31 | 2024-04-23 | 에자이 알앤드디 매니지먼트 가부시키가이샤 | 모노사이클릭 피리딘 유도체의 합성 중간체의 제조 방법 |
Also Published As
Publication number | Publication date |
---|---|
JP5925978B1 (ja) | 2016-05-25 |
AU2015304465A1 (en) | 2017-02-23 |
KR20170035927A (ko) | 2017-03-31 |
ES2914072T3 (es) | 2022-06-07 |
SG11201700703XA (en) | 2017-03-30 |
EP3184520A4 (en) | 2018-04-18 |
US20170217935A1 (en) | 2017-08-03 |
KR102344105B1 (ko) | 2021-12-29 |
EP3184520B1 (en) | 2022-03-23 |
RU2658821C1 (ru) | 2018-06-25 |
BR112017002268B1 (pt) | 2022-11-08 |
CA2956270A1 (en) | 2016-02-25 |
IL250290B (en) | 2020-06-30 |
IL250290A0 (en) | 2017-03-30 |
CN106660997B (zh) | 2019-05-21 |
AU2015304465B2 (en) | 2019-05-09 |
MX369646B (es) | 2019-11-15 |
EP3184520A1 (en) | 2017-06-28 |
MX2017001624A (es) | 2017-04-27 |
JPWO2016027781A1 (ja) | 2017-04-27 |
CN106660997A (zh) | 2017-05-10 |
US9951047B2 (en) | 2018-04-24 |
BR112017002268A2 (pt) | 2017-11-21 |
CA2956270C (en) | 2022-08-09 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP5925978B1 (ja) | 単環ピリジン誘導体の塩およびその結晶 | |
DK2805940T3 (en) | PYRAZINE CARBOXAMIDE COMPOUND | |
JP5600229B1 (ja) | 単環ピリジン誘導体 | |
JP7470058B2 (ja) | 複素環化合物 | |
JP6571077B2 (ja) | 含窒素複素環化合物 | |
WO2015016206A1 (ja) | 複素環化合物 | |
JPWO2019022179A1 (ja) | 複素環化合物 | |
KR20170043546A (ko) | 퀴나졸린 유도체 | |
WO2023060362A1 (en) | Ras inhibitors, compositions and methods of use thereof | |
JP2021533143A (ja) | Cdk8/19阻害薬 | |
WO2016027780A1 (ja) | 4-アミノピリジン誘導体 | |
CN114929675A (zh) | 作为粘着斑激酶抑制剂的新型金刚烷衍生物 | |
JP7169695B2 (ja) | ピラジノ[2,1-c][1,2,4]トリアジン化合物の結晶(1) | |
US20160318938A1 (en) | CRYSTALS (2) OF PYRAZINO[2,1-c][1,2,4]TRIAZINE COMPOUND | |
JP2023541140A (ja) | Btkを分解するための化合物の塩、その結晶形及び医薬品におけるその使用 | |
JP2006104195A (ja) | ピリミジン誘導体及び医薬 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
ENP | Entry into the national phase |
Ref document number: 2015560425 Country of ref document: JP Kind code of ref document: A |
|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 15834302 Country of ref document: EP Kind code of ref document: A1 |
|
ENP | Entry into the national phase |
Ref document number: 2956270 Country of ref document: CA |
|
WWE | Wipo information: entry into national phase |
Ref document number: 250290 Country of ref document: IL |
|
WWE | Wipo information: entry into national phase |
Ref document number: 15500429 Country of ref document: US |
|
REEP | Request for entry into the european phase |
Ref document number: 2015834302 Country of ref document: EP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2015834302 Country of ref document: EP |
|
ENP | Entry into the national phase |
Ref document number: 20177002791 Country of ref document: KR Kind code of ref document: A |
|
ENP | Entry into the national phase |
Ref document number: 2017103439 Country of ref document: RU Kind code of ref document: A |
|
WWE | Wipo information: entry into national phase |
Ref document number: MX/A/2017/001624 Country of ref document: MX |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
REG | Reference to national code |
Ref country code: BR Ref legal event code: B01A Ref document number: 112017002268 Country of ref document: BR |
|
ENP | Entry into the national phase |
Ref document number: 2015304465 Country of ref document: AU Date of ref document: 20150817 Kind code of ref document: A |
|
ENP | Entry into the national phase |
Ref document number: 112017002268 Country of ref document: BR Kind code of ref document: A2 Effective date: 20170203 |