WO2014007217A1 - イミダゾオキサジン化合物による抗腫瘍効果増強剤 - Google Patents

イミダゾオキサジン化合物による抗腫瘍効果増強剤 Download PDF

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WO2014007217A1
WO2014007217A1 PCT/JP2013/068054 JP2013068054W WO2014007217A1 WO 2014007217 A1 WO2014007217 A1 WO 2014007217A1 JP 2013068054 W JP2013068054 W JP 2013068054W WO 2014007217 A1 WO2014007217 A1 WO 2014007217A1
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Prior art keywords
phenyl
group
amino
imidazo
trans
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English (en)
French (fr)
Japanese (ja)
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市川　幸司
恵 岡田
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Taiho Pharmaceutical Co Ltd
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Taiho Pharmaceutical Co Ltd
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Priority to EP13813275.8A priority Critical patent/EP2868660B1/en
Priority to RU2015103151A priority patent/RU2618423C2/ru
Priority to KR1020167030063A priority patent/KR20160128456A/ko
Priority to DK13813275.8T priority patent/DK2868660T3/da
Priority to ES13813275.8T priority patent/ES2660215T3/es
Priority to PL13813275T priority patent/PL2868660T3/pl
Priority to AU2013284570A priority patent/AU2013284570B2/en
Priority to KR1020157001880A priority patent/KR101671761B1/ko
Priority to JP2014523736A priority patent/JP5855250B2/ja
Priority to US14/407,745 priority patent/US9375434B2/en
Priority to NO13813275A priority patent/NO2868660T3/no
Publication of WO2014007217A1 publication Critical patent/WO2014007217A1/ja
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    • A61K31/5375—1,4-Oxazines, e.g. morpholine
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    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
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    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
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    • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
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Definitions

  • the present invention relates to an antitumor effect enhancer and an antitumor agent combined with other antitumor agents.
  • antitumor agents There are a wide variety of targets for antitumor agents, and they are roughly classified into alkylating agents, platinum compounds, antimetabolites, topoisomerase inhibitors, microtubule inhibitors, antitumor antibiotics, molecular targeted drugs and the like. In recent years, an anti-tumor agent is not administered alone, but a combination therapy has been widely performed.
  • AKT is a serine threonine kinase that works downstream of phosphatidylinositol triphosphate kinase (PI3 kinase) that is activated by receiving a receptor tyrosine kinase signal.
  • PI3 kinase phosphatidylinositol triphosphate kinase
  • AKT is highly active in many cancers (renal cell cancer, stomach cancer, breast cancer, lung cancer, colon cancer, pancreatic cancer, ovarian cancer, hepatocellular carcinoma, multiple myeloma, lymphoma, leukemia, head and neck cancer, melanoma, etc.) In some cancers, gene amplification and active mutation have been reported (Non-patent Document 1).
  • Non-patent Document 2 As a function of AKT, it has been reported that AKT plays an important role in tumorigenesis such as cell proliferation, resistance to apoptosis, angiogenesis, metastasis and invasion, as well as glucose metabolism and lipid metabolism (Non-patent Document 2). ). AKT has also been reported to be highly expressed in tumors that are unresponsive to or resistant to treatment with existing antitumor agents, and in combination with existing antitumor agents including molecular target antitumor agents of AKT inhibitors The effect is expected. (Non-Patent Document 3) For example, a combination therapy of MKT-2206, which is an AKT inhibitor, and docetaxel has been reported (Non-patent Document 4, Patent Document 1).
  • any anti-tumor agent and anti-tumor agent are used in combination, their anti-tumor effects are enhanced, or even if the anti-tumor effect is enhanced, the respective toxicity is enhanced. Whether or not there is any is unknown at all and is unpredictable.
  • An object of the present invention is to provide a combination that enhances the antitumor effect of a combination of two kinds of antitumor agents without significantly exacerbating the side effects of the antitumor agents used in combination.
  • the present inventor has focused on one kind of AKT inhibitor and studied the action when the compound is used in combination with another antitumor agent.
  • the imidazooxazine compound represented by the following formula (I) or The pharmaceutically acceptable salt acts as a powerful AKT inhibitor, and in combination with other antitumor agents, it has been found that the effective area and antitumor spectrum are expanded by an excellent antitumor effect enhancing action, The present invention has been completed.
  • A, B, C, and D represent CR 1a , CR 1b , CR 1c , and CR 1d , respectively, or any one or two of A, B, C, and D are N atoms. Is replaced with At least two of R 1a , R 1b , R 1c and R 1d each represent a hydrogen atom, and the other is a halogen atom; a cyano group; a C1-6 alkyl group optionally having a hydroxyl group as a substituent; C1-6 An alkoxy group; a hydroxyl group, an amino group, a carbonyl group having either a mono or di (C1-6 alkyl) amino group or a mono or di (C1-6 alkoxy) amino group which may have a substituent as a substituent Or represents an unsaturated heterocyclic group, R 2 represents a phenyl group, a pyridyl group, or a thienyl group, R 3 represents a hydrogen atom,
  • A, B, C, and D represent CR 1a , CR 1b , CR 1c , and CR 1d , respectively, or any one or two of A, B, C, and D are Indicates that it is substituted with an N atom, At least two of R 1a , R 1b , R 1c and R 1d represent a hydrogen atom, and the other represents a chlorine atom, a fluorine atom, a cyano group, a methyl group, a hydroxymethyl group, a methoxy group, an ethoxy group, a carboxyl group, and a carbamoyl group, respectively.
  • R 2 represents a phenyl group, a pyridyl group, or a thienyl group
  • R 3 represents a hydrogen atom, a methyl group, an ethyl group, or a cyclopropyl group
  • R 4 represents a hydrogen atom or a hydroxy group.
  • an antitumor effect potentiator of another antitumor agent comprising the imidazooxazine compound or a salt thereof according to any of the following (a) to (t) as an active ingredient.
  • an imidazooxazine compound or a pharmaceutically acceptable salt thereof as described above for enhancing the antitumor effect of another antitumor agent.
  • an imidazooxazine compound or a pharmaceutically acceptable salt thereof as described above for the manufacture of an antitumor effect potentiator of another antitumor agent.
  • an imidazooxazine compound as described above or a pharmaceutically acceptable salt thereof for the manufacture of an antitumor agent in combination with another antitumor agent.
  • the other antineoplastic agent is paclitaxel, carboplatin, lapatinib, irinotecan, doxorubicin, everolimus, bortezomib, erlotinib, trastuzumab (Herceptin), metformin, docetaxel, or tegafur gimeracilo One of them.
  • a pharmaceutical composition for preventing and / or treating a tumor comprising the imidazooxazine compound or a pharmaceutically acceptable salt thereof according to any of the above and another antitumor agent is provided. Is done.
  • the method for enhancing antitumor effect comprising administering to the patient an effective amount for treatment and / or prevention of the imidazooxazine compound or a pharmaceutically acceptable salt thereof according to any of the above.
  • a therapeutically and / or prophylactically effective amount is administered to a patient in combination with any of the above-mentioned imidazooxazine compounds or pharmaceutically acceptable salts thereof and other anti-tumor agents.
  • a method for preventing and / or treating a tumor is provided.
  • the imidazooxazine compound or pharmaceutical thereof according to any of the above as a combined preparation for use simultaneously, sequentially or at intervals in the prevention and / or treatment of tumors
  • a product comprising an acceptable salt and another antitumor agent is provided.
  • the imidazooxazine compound (I) or a pharmaceutically acceptable salt thereof enhances the effects of these antitumor agents when used in combination with various antitumor agents.
  • imidazooxazine (I) does not significantly exacerbate the side effects of the combined antitumor agent, so the maximum effect of each drug alone can be achieved without reducing the effective dose of the combined antitumor agent.
  • 2) enhances the anti-tumor effect of the concomitant drug regardless of the drug sensitivity of the anti-tumor drug to be used together, and 3) the anti-tumor effect is the imidazooxazine compound (I It is also observed at low doses where it does not show antitumor effects.
  • the present invention leads to provision of a therapeutic method with high clinical usefulness such as expansion of the cancer therapeutic effect area and improvement of the therapeutic effect.
  • the term “combination” refers to an imidazooxazine compound of the present invention or a pharmaceutically acceptable salt thereof and other anti-tumors at a level sufficient to prevent and / or treat a tumor in a patient. It means that the agent can be used or administered as a single composition or as two separate compositions at the same time, or used or administered as two separate compositions, sequentially or at intervals.
  • the imidazooxazine compound of the present invention or a pharmaceutically acceptable salt thereof may be used or administered before, simultaneously with, or after other antitumor agents.
  • the imidazooxazine compound of the present invention represented by the following formula (I) or a pharmaceutically acceptable salt thereof has an antitumor effect enhancing action of other antitumor agents.
  • A, B, C, and D represent CR 1a , CR 1b , CR 1c , and CR 1d , respectively, or any one or two of A, B, C, and D Each of which is substituted with an N atom (A, B, C, and D not substituted with an N atom represent CR 1a , CR 1b , CR 1c , and CR 1d , respectively).
  • At least two of R 1a , R 1b , R 1c and R 1d each represent a hydrogen atom, and the other is a halogen atom; a cyano group; a C1-6 alkyl group optionally having a hydroxyl group as a substituent; C1-6 An alkoxy group; a hydroxyl group, an amino group, a carbonyl group having either a mono or di (C1-6 alkyl) amino group or a mono or di (C1-6 alkoxy) amino group which may have a substituent as a substituent Or represents an unsaturated heterocyclic group.
  • Examples of the halogen atom represented by R 1a , R 1b , R 1c , or R 1d include a chlorine atom, a bromine atom, a fluorine atom, or an iodine atom, and preferably a chlorine atom or a fluorine atom.
  • the C1-6 alkyl group of the “C1-6 alkyl group optionally having a hydroxyl group as a substituent” represented by R 1a , R 1b , R 1c , or R 1d is a straight chain having 1 to 6 carbon atoms Or a branched alkyl group, such as methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, or hexyl group And preferably a C1-3 alkyl group, more preferably a methyl group.
  • the number of hydroxyl groups (substituents) is 0 to 2, preferably 0 or 1.
  • C1-6 alkoxy group represented by R 1a , R 1b , R 1c , or R 1d represents a linear or branched alkoxy group having 1 to 6 carbon atoms, and includes a methoxy group, an ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, isobutoxy group, tert-butoxy group and the like are shown, preferably a C1-3 alkoxy group, more preferably a methoxy group or an ethoxy group.
  • R 1a , R 1b , R 1c , or R 1d Represented by R 1a , R 1b , R 1c , or R 1d , as a substituent, a hydroxyl group, an amino group, an optionally substituted mono- or di (C1-6 alkyl) amino group, or mono- or di- Mono or di (C1-6 alkyl) amino of “mono or di (C1-6 alkyl) aminocarbonyl group optionally having substituent (s)” in “carbonyl group having any of (C1-6 alkoxy) amino group”
  • the carbonyl group represents an aminocarbonyl group having one or two C1-6 alkyl groups as described above, preferably a mono- or di (C1-3 alkyl) aminocarbonyl group, more preferably a methylaminocarbonyl group or dimethylamino.
  • the substituent is preferably a hydroxyl group. When it has a
  • the mono- or di (C1-6 alkoxy) aminocarbonyl group represents an aminocarbonyl group having 1 or 2 C1-6 alkoxy groups, preferably a mono- or di (C1-3 alkoxy) aminocarbonyl group. More preferably, it is an ethoxyaminocarbonyl group.
  • R 1a , R 1b , R 1c , or R 1d Represented by R 1a , R 1b , R 1c , or R 1d , as a substituent, a hydroxyl group, an amino group, an optionally substituted mono- or di (C1-6 alkyl) amino group, or mono- or di-
  • a carbonyl group having any one of (C1-6 alkoxy) amino group is particularly preferably a carboxyl group, a carbamoyl group, a methylaminocarbonyl group, an ethylaminocarbonyl group, a hydroxyethylaminocarbonyl group, or an ethoxyaminocarbonyl group.
  • the “unsaturated heterocyclic group” represented by R 1a , R 1b , R 1c or R 1d is monocyclic or bicyclic having 1 to 4 heteroatoms of N, S or O
  • a 5- to 10-membered unsaturated heterocyclic group such as imidazolyl, thienyl, furyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridyl , Pyrazyl group, pyrimidinyl group, pyridazinyl group, indolyl group, isoindolyl group, indazolyl group, benzofuranyl group, benzoimidazolyl group, benzoxazolyl group, benzothiazolyl group, purinyl group, quinolyl group, isoquinolyl group, quinazolinyl group, quinoxa
  • preferred specific examples of the compound represented by the formula (I) include the following compounds.
  • salts of the imidazooxazine compound (I) include inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid , Acid addition salts with organic acids such as malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, citric acid, tartaric acid, carbonic acid, picric acid, methanesulfonic acid, paratoluenesulfonic acid, glutamic acid, sodium, Examples thereof include salts and ammonium salts with inorganic bases such as potassium, magnesium, calcium and aluminum, organic bases such as methylamine, ethylamine, meglumine and ethanolamine, or basic amino acids such as lysine, arginine and ornithine.
  • the imidazooxazine compound (I) includes optical isomers and hydrates.
  • the imidazooxazine compound (I) exhibiting an antitumor effect enhancing action according to the present invention can be produced, for example, by the following production method or the method shown in Examples. However, the method for producing the compound according to the present invention is not limited to these examples.
  • Compound (I) of the present invention can be produced using, for example, the following production method A and production method B. ⁇ Production method A>
  • This step is a method for obtaining compound 2 from aldehyde compound 1.
  • the starting compound 1 can be manufactured according to a commercial item or a well-known method.
  • the first step is a method described in the literature (for example, J. Med. Chem., Vol. 46, p. 5416, 2003, J. Org. Chem., Vol. 68, p. 5415, 2003). Or it can carry out by combining these and a conventional method.
  • the aqueous ammonia used is 1 to 10 equivalents relative to Compound 1.
  • the amount of the aqueous glyoxal solution is 1 to 10 equivalents relative to Compound 1.
  • the reaction time is 0.1 to 100 hours, preferably 0.5 to 24 hours.
  • the reaction temperature is 0 ° C. to the boiling temperature of the solvent, preferably 0 to 100 ° C.
  • the compound 2 thus obtained is isolated or purified by a known separation and purification means, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, etc., or without isolation and purification. Can be attached.
  • This step is an alkylation reaction between compound 2 and compound 3 in the presence of a base, and is a method for obtaining compound 4.
  • examples of L1 and L2 include a chlorine atom, a bromine atom and an iodine atom, which can be produced according to commercially available products or known methods.
  • Compound 3 can be used in an amount of 1 to 100 equivalents, preferably 1 to 10 equivalents, relative to Compound 2.
  • the base examples include inorganic bases such as sodium hydrogen carbonate, sodium carbonate, potassium carbonate, cesium carbonate, cesium hydroxide, trimethylamine, triethylamine, tripropylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4- (N, N- Examples thereof include organic amines such as dimethylamino) pyridine, lutidine, collidine and the like, and 1 to 100 equivalents can be used, preferably 2 to 10 equivalents.
  • inorganic bases such as sodium hydrogen carbonate, sodium carbonate, potassium carbonate, cesium carbonate, cesium hydroxide, trimethylamine, triethylamine, tripropylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4- (N, N- Examples thereof include organic amines such as dimethylamino) pyridine, lutidine, collidine and the like, and 1 to 100 equivalents can be used, preferably 2 to 10 equivalents.
  • N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide, tetrahydrofuran, 1,4-dioxane, N-methylpyrrolidin-2-one, acetonitrile, water, etc. as a solvent, either singly or in combination.
  • the reaction time is 0.1 to 100 hours, preferably 0.5 to 24 hours.
  • the reaction temperature is 0 ° C. to the boiling temperature of the solvent, preferably 0 to 100 ° C.
  • the compound 4 thus obtained can be isolated and purified by a known separation and purification means or can be subjected to the next step without isolation and purification.
  • This step is a method for obtaining compound 6 from compound 5.
  • L3 is exemplified by a chlorine atom, a bromine atom, an iodine atom, etc., and can be produced according to a commercially available product or a known method.
  • the third step can be performed by the same method as the first step.
  • This step is a reaction of compound 6 and formaldehyde in the presence of a base to obtain compound 4.
  • Formaldehyde can be used in an amount of 1 to 100 equivalents, preferably 1 to 10 equivalents, relative to compound 6.
  • formaldehyde an aqueous solution or paraformaldehyde can be used.
  • Examples of the base include bases such as sodium hydroxide, sodium carbonate, potassium hydroxide, cesium carbonate, sodium tert-butoxide, potassium tert-butoxide and the like. 1 to 100 equivalents can be used, preferably 2 to 10 equivalents. is there.
  • N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide, tetrahydrofuran, 1,4-dioxane, N-methylpyrrolidin-2-one, acetonitrile, water, etc. as a solvent, either singly or in combination.
  • the reaction time is 0.1 to 100 hours, preferably 0.5 to 24 hours.
  • the reaction temperature is 0 ° C. to the boiling temperature of the solvent, preferably 0 to 100 ° C.
  • the compound 4 thus obtained can be isolated and purified by a known separation and purification means or can be subjected to the next step without isolation and purification.
  • the halogenation method it can be carried out according to a generally known method, for example, in a reaction solvent that does not adversely influence the reaction.
  • the compound 7 thus obtained can be isolated and purified by a known separation and purification means or can be subjected to the next step without isolation and purification.
  • This step is a method for obtaining compound 8 by coupling compound 7 with arylboronic acid or arylboronic acid ester, unsaturated heterocyclic-boronic acid or unsaturated heterocyclic-boronic acid ester.
  • This step can be carried out in accordance with a generally known method (for example, Chemical-Reviews, Vol.95, 457p.2457, 1995).
  • a generally known method for example, Chemical-Reviews, Vol.95, 457p.2457, 1995.
  • a solvent that does not adversely influence the reaction in the presence of a transition metal catalyst and a base can be implemented.
  • aryl boronic acid or aryl boronic acid ester unsaturated heterocyclic-boronic acid or unsaturated heterocyclic-boronic acid ester
  • 1 to 10 equivalents can be used relative to compound 7, preferably 1 to 3 equivalents.
  • a palladium catalyst e.g., palladium acetate, palladium chloride, tetrakistriphenylphosphine palladium, etc.
  • a nickel catalyst e.g., nickel chloride, etc.
  • a ligand e.g., Triphenylphosphine, tri-tert-butylphosphine, etc.
  • metal oxides eg, copper oxide, silver oxide, etc.
  • the amount of transition metal catalyst used varies depending on the type of catalyst, but is usually about 0.0001 to 1 mol, preferably about 0.01 to 0.5 mol, relative to compound 7 (1 mol).
  • the amount of ligand used is compound 7 (1 mol). 1 mol) is usually about 0.0001 to 4 mol, preferably about 0.01 to 2 mol, and the amount of cocatalyst used is usually about 0.0001 to 4 mol, preferably about about 1 mol to compound 7 (1 mol). About 0.01 to 2 moles.
  • Examples of the base include organic amines (eg, trimethylamine, triethylamine, diisopropylethylamine, N-methylmorpholine, 1,8-diazapicyclo [5,4,0] undec-7-ene, pyridine, N, N-dimethylaniline.
  • organic amines eg, trimethylamine, triethylamine, diisopropylethylamine, N-methylmorpholine, 1,8-diazapicyclo [5,4,0] undec-7-ene, pyridine, N, N-dimethylaniline.
  • alkali metal salts e.g., sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium phosphate, potassium phosphate, sodium hydroxide, potassium hydroxide, etc.
  • metal hydrides e.g., Potassium hydride, sodium hydride, etc.
  • alkali metal alkoxides eg, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, etc.
  • alkali metal disilazides eg, lithium disilazide, sodium disulfide
  • Silazide, potassium disilazide, etc. Of these, alkali metal salts such as potassium carbonate, cesium carbonate, sodium phosphate and potassium phosphate, alkali metal alkoxides such as sodium tert-butoxide and potassium tert-butoxide, organic amines such as triethylamine and diisopropyleth
  • the solvent is not particularly limited as long as it does not adversely affect the reaction.
  • hydrocarbons eg, benzene, toluene, xylene, etc.
  • halogenated hydrocarbons eg, chloroform, 1,2-dichloroethane, etc.
  • Nitriles e.g., acetonitrile, etc.
  • ethers e.g., dimethoxyethane, tetrahydrofuran, etc.
  • alcohols e.g., methanol, ethanol, etc.
  • aprotic polar solvents e.g., dimethylformamide, dimethyl sulfoxide, hexamethylphosphoramide
  • Etc. water or a mixture thereof.
  • the reaction time is 0.1 to 100 hours, preferably 0.5 to 24 hours.
  • the reaction temperature is 0 ° C. to the boiling temperature of the solvent, preferably 0 ° C. to 150 ° C.
  • the compound 8 thus obtained can be isolated and purified by a known separation and purification means or can be subjected to the next step without isolation and purification.
  • the seventh step can be performed by the same method as the fifth step.
  • This step is a method for converting any of A1 to D1 of Compound 8 into A1 to D1 by performing a coupling reaction or the like using a generally known method.
  • Compound 10 is obtained by a coupling reaction under a transition metal catalyst.
  • the compound 10 thus obtained can be isolated and purified by a known separation and purification means or can be subjected to the next step without isolation and purification.
  • the ninth step can be performed by the same method as the fifth step.
  • This step is a method of obtaining compound 13 by a coupling reaction between compound 9 and compound 12.
  • Compound 12 is prepared by a method described in the literature (for example, International Publication No. 2008-070016, International Publication No. 2009-148877, International Publication No. 2009-148916, International Publication No. 2010-088177, International Publication No. 2010-114780). , International Publication No. 2010-104933) or a method according to these methods.
  • This step can be performed by the same method as the sixth step.
  • the compound 13 thus obtained can be isolated and purified by a known separation and purification means or can be subjected to the next step without isolation and purification.
  • This step is a method of converting any of A to D of compound 9 into any of A2 to D2 by performing a functional group conversion reaction or the like using a generally known method.
  • the compound 11 thus obtained can be isolated and purified by a known separation and purification means or can be subjected to the next step without isolation and purification.
  • the twelfth step can be performed by the same method as the tenth step.
  • This step is a method of obtaining compound 14 by hydrolysis under basic conditions when any of A to D of compound 13 has an ester group.
  • sodium hydrogen carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide and the like can be used in an amount of 1 to 100 equivalents, preferably 1 to 30 equivalents.
  • the reaction time is 0.1 to 100 hours, preferably 0.5 to 24 hours.
  • the reaction temperature is 0 ° C. to the boiling temperature of the solvent, preferably 0 ° C. to 100 ° C.
  • the compound 14 thus obtained can be isolated and purified by a known separation and purification means, or can be subjected to the next step without isolation and purification.
  • This step is a method of obtaining compound 13 by subjecting compound 14 to an amidation reaction with an amine in an organic solvent.
  • the method of amidation can be carried out by a conventionally known method, and a method of reacting compound 14 with the corresponding amine in the presence of a condensing agent is exemplified.
  • a method of reacting compound 14 with the corresponding amine in the presence of a condensing agent is exemplified.
  • the compound 13 thus obtained can be isolated and purified by a known separation and purification means or can be subjected to the next step without isolation and purification.
  • This step is a method of obtaining compound (I) by deprotecting the amino group protection of compound 13.
  • the deprotection can be performed by a generally known method such as the method described in Protective Groups in Organic Synthesis, TW Greene, John Wiley & Sons (1981), or a method analogous thereto.
  • the protecting group examples include tert-butyloxycarbonyl, phthalimide and the like.
  • the acid examples include hydrochloric acid, acetic acid, trifluoroacetic acid, sulfuric acid, tosylic acid and the like.
  • the amount of acid used is preferably about 1 to 100 equivalents relative to compound 12.
  • the solvent used in the reaction is not particularly limited as long as it does not adversely influence the reaction.
  • alcohols eg, methanol, etc.
  • hydrocarbons eg, benzene, toluene, xylene, etc.
  • halogenated hydrocarbons eg, , Methylene chloride, chloroform, 1,2-dichloroethane, etc.
  • nitriles eg, acetonitrile, etc.
  • ethers eg, dimethoxyethane, tetrahydrofuran, etc.
  • aprotic polar solvents eg, N, N-dimethylformamide, Dimethyl sulfoxide, hexamethylphosphoramide, etc.
  • the reaction time is 0.1 to 100 hours, preferably 0.5 to 24 hours.
  • the reaction temperature is 0 to 100 ° C., preferably 0 to 50 ° C.
  • hydrazine treatment can be performed.
  • the amount of hydrazine used is preferably 1 to 100 equivalents relative to compound 12.
  • the reaction can be synthesized by heating reaction using a microwave reaction apparatus and the like, and the solvent used for the reaction is not particularly limited as long as it does not adversely affect the reaction.
  • the solvent used for the reaction is not particularly limited as long as it does not adversely affect the reaction.
  • carbonization of alcohols eg, methanol, ethanol, etc.
  • Hydrogens eg, benzene, toluene, xylene, etc.
  • halogenated hydrocarbons eg, methylene chloride, chloroform, 1,2-dichloroethane, etc.
  • nitriles eg, acetonitrile, etc.
  • ethers eg, dimethoxyethane, etc.
  • Tetrahydrofuran etc.
  • aprotic polar solvents eg, N, N-dimethylformamide, dimethyl sulfoxide, hexamethylphosphoramide, etc.
  • the reaction time is 0.1 to 100 hours,
  • the compound (I) thus obtained can be isolated and purified by known separation and purification means such as concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography and the like.
  • the imidazooxazine compound (I) is an antitumor agent having an excellent AKT inhibitory action and reduced side effects, but when used in combination with various other antitumor agents (hereinafter referred to as antitumor agent A). It has an action of enhancing the antitumor effect of the antitumor agent A without showing a marked increase in toxicity.
  • the antitumor agent A whose action is enhanced by the imidazooxazine compound (I) is not particularly limited.
  • antitumor antibiotics such as doxorubicin and epirubicin
  • alkylating agents such as cyclophosphamide and nimustine
  • cisplatin Platinum preparations such as carboplatin and oxaliplatin
  • 5-fluorouracil (5-FU) tegafur, gimeracil and oteracil potassium (that is, a combination drug containing tegafur, gimeracil and oteracil potassium)
  • TS-1 generic name “tegafur gimeracil” ⁇ Oteracil potassium combination ”(trade name: TS-1)
  • tegafur uracil ie, combination containing tegafur and uracil
  • UFT generic name“ tegafur uracil combination
  • Capecitabine Pyrimidine antimetabolites such as doxorubicin and epirubici
  • Antitumor agents A whose actions are enhanced by imidazooxazine compound (I) include paclitaxel, carboplatin, lapatinib, irinotecan, doxorubicin, everolimus, bortezomib, erlotinib, trastuzumab (Herceptin, Herceptin), metformin, docetaxel, Gimeracil / oteracil potassium combination agent is preferable.
  • the malignant tumor that can be treated together with the antitumor agent A whose action is enhanced by the imidazooxazine compound (I).
  • the malignant tumor that can be treated together with the antitumor agent A whose action is enhanced by the imidazooxazine compound (I).
  • head and neck cancer esophageal cancer, stomach cancer, colon cancer, rectal cancer, hepatocellular carcinoma , Gallbladder and bile duct cancer, pancreatic cancer, lung cancer, breast cancer, ovarian cancer, cervical cancer, endometrial cancer, renal cancer, bladder cancer, prostate cancer, testicular tumor, bone and soft tissue sarcoma, leukemia, malignant lymphoma, multiple myeloma , Skin cancer, brain tumor and the like.
  • the present invention relates to an antitumor effect potentiator of another antitumor agent comprising the imidazooxazine compound (I) or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention relates to an antitumor agent comprising the imidazooxazine compound (I) or a pharmaceutically acceptable salt thereof in combination with another antitumor agent.
  • the present invention relates to a pharmaceutical composition for preventing and / or treating a tumor comprising the imidazooxazine compound (I) or a pharmaceutically acceptable salt thereof and another antitumor agent.
  • the present invention relates to the use of the imidazooxazine compound (I) or a pharmaceutically acceptable salt thereof for enhancing the antitumor effect of another antitumor agent.
  • the present invention relates to the use of the imidazooxazine compound (I) or a pharmaceutically acceptable salt thereof for the production of an antitumor effect enhancer of another antitumor agent.
  • the present invention provides an antitumor effect enhancement comprising administering to the patient an amount effective for treatment and / or prevention of the imidazooxazine compound (I) or a pharmaceutically acceptable salt thereof. Regarding the method.
  • the present invention provides the patient with an amount effective for treatment and / or prevention by combining the imidazooxazine compound (I) or a pharmaceutically acceptable salt thereof with another antitumor agent.
  • the present invention relates to a method for preventing and / or treating a tumor, comprising administration.
  • the present invention provides the imidazooxazine compound (I) or a pharmaceutical thereof as a combined preparation for use simultaneously, sequentially or at intervals in preventing and / or treating a tumor. Relates to a product comprising a pharmaceutically acceptable salt and other antineoplastic agents.
  • an antitumor agent having an enhanced antitumor effect can be obtained.
  • a new antitumor drug it may be a one-part preparation form containing imidazooxazine compound (I) or a pharmaceutically acceptable salt thereof and antitumor agent A, or an imidazooxazine compound
  • the preparation containing (I) or a pharmaceutically acceptable salt thereof and the preparation containing the antitumor agent A may be in separate preparation forms.
  • the administration means of the composition containing the imidazooxazine compound (I) and the administration means of the composition containing the antitumor agent A may be the same or different (for example, oral administration and injection). .
  • the imidazooxazine compound (I) or a pharmaceutically acceptable salt thereof is contained in a pharmaceutical composition, it can be combined with a pharmaceutical carrier as necessary, and various administration forms can be adopted depending on the purpose of prevention or treatment.
  • administration forms include oral preparations, injections, suppositories, ointments, patches, and the like, with oral preparations being preferred.
  • Each of these dosage forms can be produced by a conventional formulation method known to those skilled in the art.
  • the pharmaceutical carrier various organic or inorganic carrier substances commonly used as pharmaceutical materials are used. Excipients, binders, disintegrants, lubricants, colorants in solid preparations; solvents, dissolution aids, suspensions in liquid preparations. It is blended as a turbidity agent, tonicity agent, buffering agent, soothing agent and the like. Moreover, formulation additives such as preservatives, antioxidants, colorants, sweeteners, stabilizers and the like can be used as necessary.
  • a tablet is prepared by a conventional method. Coated tablets, granules, powders, capsules and the like can be produced.
  • excipients include lactose, sucrose, D-mannitol, glucose, starch, calcium carbonate, kaolin, microcrystalline cellulose, and anhydrous silicic acid.
  • binder examples include water, ethanol, 1-propanol, 2-propanol, simple syrup, glucose solution, ⁇ -starch solution, gelatin solution, D-mannitol, carboxymethylcellulose, hydroxypropylcellulose, hydroxypropyl starch, methylcellulose, ethylcellulose, Shellac, calcium phosphate, polyvinylpyrrolidone and the like can be mentioned.
  • disintegrant examples include dry starch, sodium alginate, agar powder, sodium bicarbonate, calcium carbonate, sodium lauryl sulfate, stearic acid monoglyceride, and lactose.
  • lubricant examples include purified talc, sodium stearate, magnesium stearate, borax, polyethylene glycol and the like.
  • Examples of the colorant include titanium oxide and iron oxide.
  • flavoring or flavoring agents examples include sucrose, orange peel, citric acid, and tartaric acid.
  • the coating can be applied to the oral preparation by a known method for the purpose of enteric coating or to maintain the effect.
  • a coating agent include hydroxypropylmethylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, polyoxyethylene glycol, Tween80 (registered trademark), and the like.
  • pH adjusters When preparing injections, add pH adjusters, buffers, stabilizers, tonicity agents, local anesthetics, etc. to imidazooxazine compound (I), and use subcutaneous, intramuscular and intravenous methods by conventional methods.
  • An injection can be produced.
  • examples of the pH adjuster and buffer include sodium citrate, sodium acetate, and sodium phosphate.
  • examples of the stabilizer include sodium pyrosulfite, EDTA, thioglycolic acid, thiolactic acid and the like.
  • local anesthetics include procaine hydrochloride and lidocaine hydrochloride.
  • isotonic agents include sodium chloride, glucose, D-mannitol, glycerin and the like.
  • a formulation carrier known in the art such as polyethylene glycol, lanolin, cocoa butter, fatty acid triglyceride and the like is added to the compound of the present invention, and an interface such as Tween 80 (registered trademark) as necessary. After adding an activator etc., it can manufacture by a conventional method.
  • bases, stabilizers, wetting agents, preservatives and the like that are usually used for the compound of the present invention are blended as necessary, and mixed and formulated by a conventional method.
  • the base include liquid paraffin, white petrolatum, white beeswax, octyldodecyl alcohol, paraffin and the like.
  • the preservative include methyl paraoxybenzoate, ethyl paraoxybenzoate, and propyl paraoxybenzoate.
  • the ointment, cream, gel, paste or the like may be applied to a normal support by a conventional method.
  • a woven fabric, nonwoven fabric, soft vinyl chloride, polyethylene, polyurethane film or foam sheet made of cotton, suf, chemical fiber is suitable.
  • the agent of the present invention can be used for mammals including humans (for example, humans, cows, horses, pigs, monkeys, dogs, cats, mice, rats, rabbits, goats, sheep, etc.), preferably humans Used.
  • the amount of the imidazooxazine compound (I) to be blended in each dosage unit form is not constant depending on the symptoms of the patient to which the compound is to be applied, or its dosage form, but generally per oral dosage unit form.
  • the dosage is about 0.05 to 1,000 mg
  • the injection is about 0.01 to 500 mg
  • the suppository is about 1 to 1,000 mg.
  • the “low dose in which the imidazooxazine compound (I) itself does not exhibit an antitumor effect” is about 0.05 to 20 mg for an oral preparation per dosage unit form.
  • the daily dose of the drug having the above dosage form varies depending on the patient's symptoms, body weight, age, sex, etc., and cannot be determined unconditionally, but is usually about 0.05 to 5,000 mg per day for an adult (body weight 50 kg). 0.1 to 1,000 mg is preferable, and it is preferable to administer this once a day or in 2 to 3 divided doses.
  • the preparations can be used simultaneously, or at any time before or after administration of one component.
  • Other ingredients can be administered.
  • each formulation can be administered simultaneously, sequentially or at intervals.
  • the administration or blending ratio of the imidazooxazine compound (I) or a pharmaceutically acceptable salt thereof and the antitumor agent A is not particularly limited as long as the antitumor effect is enhanced, but the antitumor agent A1 mol
  • the imidazooxazine compound (I) or a pharmaceutically acceptable salt thereof may be about 0.001 to 100 mol, preferably about 0.005 to 50 mol.
  • the amount of imidazooxazine compound (I) or a pharmaceutically acceptable salt thereof is about 0.05 to 50 mol per mol of paclitaxel.
  • the amount of the imidazooxazine compound (I) or a pharmaceutically acceptable salt thereof is about 0.005 to 5 mol with respect to 1 mol of carboplatin.
  • the imidazooxazine compound (I) or a pharmaceutically acceptable salt thereof is about 0.01 to 20 moles per mole of lapatinib.
  • the amount of the imidazooxazine compound (I) or a pharmaceutically acceptable salt thereof is about 0.05 to 30 mol with respect to 1 mol of irinotecan.
  • the amount of the imidazooxazine compound (I) or a pharmaceutically acceptable salt thereof is about 0.05 to 20 mol per mol of doxorubicin.
  • the amount of the imidazooxazine compound (I) or a pharmaceutically acceptable salt thereof is about 0.05 to 20 moles per mole of everolimus.
  • the amount of imidazooxazine compound (II) or a pharmaceutically acceptable salt thereof is about 1 to 500 mol per mol of bortezomib.
  • the amount of the imidazooxazine compound (II) or a pharmaceutically acceptable salt thereof is about 0.01 to 10 moles per mole of erlotinib.
  • antitumor agent A is trastuzumab (Herceptin)
  • the amount of the imidazooxazine compound (I) or a pharmaceutically acceptable salt thereof is about 0.00001 to 0.01 mol with respect to 1 mol of metformin.
  • the amount of the imidazooxazine compound (I) or a pharmaceutically acceptable salt thereof is about 0.001 to 0.3 mol with respect to 1 mol of docetaxel.
  • the amount of the imidazooxazine compound (I) or a pharmaceutically acceptable salt thereof is about 0.05 to 50 mol with respect to 1 mol of tegafur. .
  • the present invention will be described in more detail with reference examples, examples, and test examples, but the present invention is not limited to these examples.
  • the maximum tolerated dose (MTD) or physical properties indicated by a paper report etc. The maximum dose that could be administered was used.
  • Antitumor agents have extremely close doses and maximum toxic doses, and are generally evaluated in the vicinity of MTD in order to evaluate the maximum antitumor effect of the drug in an animal model. Is synonymous with MTD and maximum effect dose.
  • Kieselgel TM 60F254, Art.5744 manufactured by Merck or NH2 silica gel 60F254 plate Wako manufactured by Wako was used.
  • DMSO-d6 Heavy dimethyl sulfoxide CDCl3: Deuterated chloroform THF: tetrahydrofuran DMF: N, N-dimethylformamide DMSO: Dimethyl sulfoxide WSC: 1- (3-Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride HOBt: 1-hydroxybenzotriazole monohydrate Pd (PPh3) 4: Tetrakistriphenylphosphine palladium
  • the obtained residue was purified by silica gel chromatography (hexane: ethyl acetate) to obtain a corresponding imidazophenol compound.
  • the obtained imidazophenol was used in the next reaction without further purification.
  • potassium carbonate (1.98 g) and diiodomethane (0.44 mL) were added, and the mixture was stirred at 80 ° C. for 3 hours.
  • the reaction mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate.
  • the combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • Reference example 2 Reference Example 2 (1) 2-Bromo-3- (1H-imidazol-2-yl) pyridine 2-bromonicotinaldehyde (10 g) in methanol (90 mL), 28% aqueous ammonia (50 mL) and 40% aqueous glyoxal (50 mL) was added, and the mixture was stirred at room temperature for 14 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (hexane: ethyl acetate) to obtain the desired product (4.62 g, yield 38%) as a colorless solid.
  • Reference Example 2 (2) 5H-imidazo [1,2-c] pyrido [3,2-e] [1,3] oxazine Reference Example 2 (1) (44.8 mg) in 2-propanol (2.0 mL) Potassium hydroxide (66 mg) and 37% formalin aqueous solution (0.20 mL) were added, and the mixture was heated with stirring at 80 ° C. for 14 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel chromatography (hexane: ethyl acetate) to obtain the desired product (16.7 mg, 48% yield) as a colorless solid.
  • Reference Examples 20 and 21 were synthesized by the methods shown below in accordance with the method of Reference Example 11 or 2, using commercially available raw materials in the table or raw materials that can be synthesized by known methods. did.
  • Reference Example 20 Reference Example 20 (1) 2- (1H-imidazol-2-yl) -3-methoxypyrazine 3-methoxypyrazine-2-carbaldehyde (480 mg) in methanol (7.5 mL) in 40% glyoxal aqueous solution (0.80 mL) Then, 28% aqueous ammonia (1.94 mL) was slowly added dropwise at 8 ° C. The reaction solution was stirred for 10 minutes and then stirred at room temperature for 1 hour. The residue obtained by concentrating the reaction mixture under reduced pressure was purified by basic silica gel chromatography (chloroform: methanol) to obtain the desired product (410 mg, 66% yield) as a pale brown amorphous.
  • Reference Example 20 (2) 5H-imidazo [1,2-c] pyrazino [2,3-e] [1,3] oxazine Reference Example 20 (1) (460 mg) in 5 M hydrochloric acid (15 mL) It stirred for 30 minutes at 120 degreeC using the reaction apparatus. The reaction mixture was cooled, azeotroped with ethanol, and concentrated under reduced pressure. To a DMF (50 mL) solution of the obtained residue, potassium carbonate (1.79 g) and diiodomethane (0.42 mL) were added, and the mixture was stirred at 80 ° C. for 2 hours. The reaction mixture was cooled to room temperature, diluted with water and chloroform, and extracted with chloroform.
  • Reference Example 21 (1) Methyl 6-bromo-3- (methoxymethoxy) picolinate Methyl 6-bromo-3-hydroxypyridine-2-carboxylate (970 mg) in chloroform (20 mL) was added diisopropylethylamine (1.46 mL). After adding nitrogen atmosphere, the reaction solution was cooled to 0 ° C., and chloromethoxymethane (0.38 mL) was added. The reaction solution was stirred at 0 ° C. for 5 minutes and then stirred at room temperature for 1 hour. The reaction mixture was cooled to 0 ° C., diluted with water, and extracted with chloroform.
  • Reference Example 21 6-Bromo-3- (methoxymethoxy) picolinaldehyde Reference Example 21 (1) (1.22 g) in THF (20 mL) was placed in a nitrogen atmosphere, and then the reaction solution was cooled to -78 ° C. Then, a toluene solution (5.08 mL) of 0.99 M diisobutylaluminum hydride was added. The reaction solution was stirred at ⁇ 78 ° C. for 1 hour. Furthermore, a toluene solution (0.51 mL) of 0.99 M diisobutylaluminum hydride was added, and the mixture was stirred at ⁇ 78 ° C. for 1 hour.
  • Reference Example 21 (3) 6-Bromo-2- (1H-imidazol-2-yl) -3- (methoxymethoxy) pyridine
  • Reference Example 21 (2) (1.03 g) in methanol (16 mL) in 40% glyoxal aqueous solution (0.96 mL) was added, and 28% aqueous ammonia (2.32 mL) was slowly added dropwise under ice cooling. After stirring at room temperature for 4 hours, the reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by basic silica gel chromatography (chloroform: methanol) to obtain the desired product (0.91 g, yield 77%) as a pale tan color. Obtained as a solid.
  • Reference Example 21 (4) 9-Bromo-5H-imidazo [1,2-c] pyrido [2,3-e] [1,3] oxazine Reference Example 21 (3) (0.91 g) in chloroform (12 mL) To the solution, trifluoroacetic acid (6.0 mL) was added dropwise under ice cooling. After stirring at room temperature for 14 hours, the reaction mixture was azeotroped with toluene-chloroform and concentrated under reduced pressure. DMF (20 mL), potassium carbonate (2.22 g) and diiodomethane (0.52 ml) were added to the resulting residue, and the mixture was stirred at 80 ° C. for 1.5 hours.
  • Reference Example 22 (1) 3-Bromo-10-fluoro-5H-benzo [e] imidazo [1,2-c] [1,3] oxazine Chloroform (7.0 mL) of the compound (349 mg) obtained in Reference Example 1 The solution was cooled to 0 ° C., N-bromosuccinimide (343 mg) was added, and the mixture was stirred at 0 ° C. for 1 hour. The reaction mixture was purified by silica gel chromatography (hexane: ethyl acetate) to obtain the desired product (360 mg, yield 73%) as a colorless solid.
  • the obtained residue was purified by silica gel chromatography (hexane: ethyl acetate) to obtain a corresponding coupled product.
  • the obtained coupled product was used for the next reaction without further purification.
  • a chloroform (5.0 mL) solution of the obtained coupling product was cooled to 0 ° C., N-bromosuccinimide (380 mg) was added, and the mixture was stirred at room temperature for 1 hour.
  • the reaction mixture was purified by silica gel chromatography (hexane: ethyl acetate) to obtain the desired product (602 mg, yield 91%) as a colorless solid.
  • Reference Example 23 (2) 9-Bromo-3-phenyl-5H-benzo [e] imidazo [1,2-c] [1,3] oxazine
  • Reference Example 23 (1) (9.44 g) of 1,4-dioxane (250 mL), water (40 mL) solution, phenylboronic acid (3.35 g) and cesium carbonate (23.3 g) were added, and the mixture was brought to a nitrogen atmosphere, and then Pd (PPh3) 4 (3.30 g) was added, The mixture was stirred at 50 ° C. for 5 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • Reference Example 23 (3) Methyl 3-phenyl-5H-benzo [e] imidazo [1,2-c] [1,3] oxazine-9-carboxylate Reference Example 23 (2) (5.0 g) in DMF (30 mL ), Methanol (30 mL) solution, diisopropylethylamine (8.0 mL) and [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II) dichloromethane complex (1.38 g) were added to form a carbon monoxide atmosphere. Then, it stirred at 70 degreeC for 28 hours.
  • the reaction mixture was cooled to room temperature, diluted with saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (hexane: ethyl acetate) to obtain the desired product (2.12 g, 45%) as a colorless solid.
  • Reference Example 23 (4) Methyl 2-bromo-3-phenyl-5H-benzo [e] imidazo [1,2-c] [1,3] oxazine-9-carboxylate Reference Example 23 (3) (1.0 g) N-bromosuccinimide (754 mg) was added to a chloroform (16 mL) solution, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was filtered, and the residue was washed with chloroform to obtain the desired product (800 mg, yield 64%) as a colorless solid.
  • Reference Example 24 (2-Bromo-3-phenyl-5H-benzo [e] imidazo [1,2-c] [1,3] oxazin-9-yl) methanol
  • Reference Example 23 (4) (550 mg) in methylene chloride (14 mL) The solution was cooled to 0 ° C, 0.99 M diisobutylaluminum hydride in toluene (4.3 mL) was added, and the mixture was stirred at 0 ° C for 1 hr. A saturated aqueous Rochelle salt solution was added to the reaction mixture, and the mixture was further stirred at room temperature for 2 hours.
  • the reaction mixture was extracted with ethyl acetate, and the combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • the obtained residue was purified by silica gel chromatography (hexane: ethyl acetate) to give the object product (397 mg, yield 78%) as a colorless solid.
  • Reference Example 25 Synthesis of 2-bromo-3-phenyl-5H-benzo [e] imidazo [1,2-c] [1,3] oxazine-9-carbonitrile 1 of Reference Example 23 (2) (500 mg) under nitrogen atmosphere Zinc cyanide (360 mg) and di-tert-butylpalladium (78.2 mg) were added to a solution of 1,4-dioxane (3.0 mL) and DMF (3.0 mL), and the mixture was stirred at 100 ° C. for 3 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, and filtered.
  • the filtrate was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • the obtained residue was purified by silica gel chromatography (hexane: ethyl acetate) to obtain the corresponding cyano compound.
  • the cyano compound was used in the next reaction without further purification.
  • N-bromosuccinimide (352 mg) was added to a chloroform (8.0 mL) solution of the obtained cyano compound, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was filtered, and the residue was washed with chloroform to give the object product (207 mg, yield 36%) as a colorless solid.
  • Reference Example 28 9-methyl-5H-imidazo [1,2-c] pyrido [2,3-e] [1,3] oxazine
  • Reference Example 21 (4) (50 mg) of 1,4-dioxane (2.0 mL), water ( 0.32 mL) methylboronic acid (17.8 mg) and cesium carbonate (162 mg) were added to the solution, and the mixture was brought to a nitrogen atmosphere. Methyl boronic acid (17.8 mg) was added to the reaction mixture, and the mixture was stirred at 110 ° C. for 2 hours. Further, methyl boronic acid (17.8 mg) was added, and the mixture was stirred at 110 ° C. for 2 hours.
  • Reference Example 29 9-methoxy-5H-imidazo [1,2-c] pyrido [2,3-e] [1,3] oxazine
  • methanol 2.0 mL
  • 25 wt% sodium methoxy Of methanol 0.36 mL
  • the reaction mixture was cooled to room temperature, diluted with water and chloroform, and extracted with chloroform.
  • the combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • Reference Example 56 Reference Example 56 (1) 1- (4-Bromophenyl) cyclobutanecarbonitrile A solution of potassium hydroxide (56.5 g) and tetrabutylammonium bromide (2.92 g) in toluene (400 mL) and water (30 mL) was heated to 70 ° C. Then, 1,3-dibromopropane (39.0 g) and 2- (4-bromophenyl) acetonitrile (35.5 g) were sequentially added, and the mixture was stirred at 100 ° C. for 3 hours. The reaction mixture was cooled to 80 ° C., heptane (100 mL) was added, and the mixture was further cooled to room temperature.
  • the reaction mixture was filtered and washed with hexane, and then the organic layer was separated.
  • the obtained organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • the obtained residue was purified by silica gel chromatography (hexane: ethyl acetate) to give the object product (24.0 g, yield 56%) as a colorless oil.
  • Reference Example 56 (2) 1- (4-Bromophenyl) cyclobutanecarboxylic acid To a solution of Reference Example 56 (1) (24.0 g) in butanol (100 mL), 50% aqueous sodium hydroxide solution (35 mL) was added, and the mixture was heated to 120 ° C. And stirred for 14 hours. After cooling to room temperature, water (100 mL) was added to the reaction mixture, and after washing with ether, the ether layer was further extracted twice with 1N aqueous sodium hydroxide solution (50 mL). To the combined aqueous layer was added 5M hydrochloric acid to adjust the pH to 2, followed by extraction with ethyl acetate.
  • Reference Example 56 (4) tert-butyl 1- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) cyclobutylcarbamate Reference Example 56 (3) (3.21 g) in DMF (25 mL), potassium acetate (2.41 g), 4,4,4 ', 4', 5,5,5 ', 5'-octamethyl-2,2'-bi (1 , 3,2-Dioxaborolane) (6.25 g), and under a nitrogen atmosphere, [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II) dichloromethane complex (360 mg) was added at 80 ° C.
  • Reference Example 57 Reference Example 57 (1) Cis-1- (4-bromophenyl) -3-hydroxycyclobutanecarboxylic acid 2M Isopropylmagnesium chloride To tetrahydrofuran solution (560mL), THF of 4-bromophenylacetic acid (107.8g) under ice-cooling and stirring (100 mL) The solution was added dropwise, and the mixture was warmed to room temperature and stirred for 1 hour. Epichlorohydrin (73 mL) was added dropwise to the resulting suspension at room temperature, the temperature was raised to 26 ° C. by reaction heat, and the mixture was cooled and stirred for 3 hours while maintaining the temperature.
  • Reference Example 57 (2) Methyl cis-1- (4-bromophenyl) -3-hydroxycyclobutanecarboxylate Reference Example 57 (1) (116.0 g) was dissolved in methanol (500 mL), and concentrated sulfuric acid (3.5 mL) was added and heated to reflux overnight. The reaction mixture was concentrated under reduced pressure to reduce methanol, diluted with water, and extracted with ethyl acetate. The combined organic layers were washed with 1M aqueous sodium hydroxide solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the desired product (112.5 g, yield 99%) as a pale yellow solid.
  • Reference Example 57 (3) Methyl 1- (4-bromophenyl) -3-oxocyclobutylcarboxylate Reference Example 57 (2) (112.5 g) was dissolved in chloroform (500 mL), and N-methylmorpholine-N- Oxide (63.3 g) and powdered molecular sieve 4A (120 g) were added. The mixture was ice-cooled, tetra-n-propylammonium pearlate (2.76 g) was added, and the mixture was stirred for 24 hours while warming to room temperature.
  • Reference Example 57 (4) Trans-3-amino-3- (4-bromophenyl) -1-cyclopropylcyclobutanol Reference Example 57 (3) (18.57 g) in toluene (200 mL) was cooled to ⁇ 40 ° C. 0.7M cyclopropylmagnesium bromide in THF (310 ml) was added dropwise. After stirring at ⁇ 40 ° C. for 15 minutes and at 0 ° C. for 3 hours, the reaction mixture was carefully added with ice, then saturated aqueous ammonium chloride solution, and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure.
  • the obtained residue was dissolved in 1,4-dioxane (100 ml), 1M aqueous sodium hydroxide solution (150 ml) was added at room temperature, and the mixture was stirred overnight.
  • the reaction mixture was concentrated under reduced pressure to remove 1,4-dioxane, and the aqueous layer was washed with toluene.
  • the obtained aqueous solution was acidified with 2M hydrochloric acid, and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure.
  • the obtained residue was dissolved in 1,4-dioxane (215 mL), N, N-diisopropylethylamine (7.60 ml) and diphenylphosphoric acid azide (8.77 ml) were added at room temperature, and then at room temperature for 4 hours, then 63 After stirring at 4 ° C. for 4 hours, the mixture was cooled to room temperature. The obtained reaction solution was added dropwise to vigorously stirred 0.5M hydrochloric acid (1000 ml) and stirred at room temperature for 3 hours.
  • reaction mixture was washed with ethyl acetate, 2M aqueous sodium hydroxide solution was added to the resulting aqueous solution to make it basic, and sodium chloride was dissolved until saturation, followed by extraction with chloroform.
  • the combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the desired product (5.52 g, yield 30%) as a pale yellow oil.
  • Reference Example 57 2- (trans-1- (4-bromophenyl) -3-cyclopropyl-3-hydroxycyclobutyl) isoindoline-1,3-dione Chloroform of Reference Example 57 (5) (882 mg) (15.6 mL) To the solution were added triethylamine (0.52 mL) and N-ethoxycarbonylphthalimide (683 mg), and the mixture was stirred at 70 ° C. for 38 hours. The reaction mixture was cooled, diluted with water, and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure.
  • Reference Example 57 2- (trans-3-cyclopropyl-3-hydroxy-1- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl ) Cyclobutyl) isoindoline-1,3-dione
  • Reference Example 57 (5) (1.26 g) in 1,4-dioxane (15 mL), 4,4,4 ′, 4 ′, 5,5,5 ′, 5'-octamethyl-2,2'-bi (1,3,2-dioxaborolane) (1.14g)
  • potassium acetate (883mg)
  • (1,1'-bis (diphenylphosphino) ferrocene) dichloropalladium (II) (245 mg) was added, and the mixture was stirred at 80 ° C.
  • Reference Example 58 Reference Example 58 (1) Trans-1- (4-Bromophenyl) -3-hydroxy-3-methylcyclobutanecarboxylic acid A solution of Reference Example 57 (3) (11.62 g) in THF (210 ml) was cooled to ⁇ 40 ° C. 3M methylmagnesium chloride in THF (48 ml) was added dropwise. After stirring at ⁇ 40 ° C. for 15 minutes and at 0 ° C. for 2 hours, the reaction mixture was carefully added with ice and then saturated aqueous ammonium chloride solution, and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure.
  • the obtained residue was dissolved in 1,4-dioxane (60 ml), 1M aqueous sodium hydroxide solution (62 ml) was added at room temperature, and the mixture was stirred overnight.
  • the resulting reaction solution was concentrated under reduced pressure to remove 1,4-dioxane, poured into a 0.5 M aqueous sodium hydroxide solution, and the aqueous layer was washed with ethyl acetate.
  • the obtained basic aqueous solution was acidified with 2M hydrochloric acid, and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure.
  • Reference Example 58 (2) trans-3-amino 3- (4-bromophenyl) -1-methylcyclobutanol Reference Example 58 (1) (4.28 g) in 1,4-dioxane (60 mL) solution in triethylamine (2.20 mL) ) And diphenylphosphoryl azide (3.40 mL) were added, and the mixture was stirred at 80 ° C. for 2 hours. The reaction mixture was cooled to room temperature, then added to ice-cooled 1M hydrochloric acid (60 mL), and stirred at room temperature for 2 hours. Water was added to the reaction mixture, washed with diethyl ether, made basic with 5M aqueous sodium hydroxide solution, and extracted with chloroform.
  • Reference Example 58 (3) tert-butyl trans-1- (4-bromophenyl) -3-hydroxy-3-methylcyclobutylcarbamate
  • Reference Example 58 (2) (3.23 g) of 1,4-dioxane (63 mL) Di tert-butyl dicarbonate (3.30 g) was added to the solution and stirred at 70 ° C. for 3 hours. The reaction mixture was concentrated under reduced pressure and recrystallized from hexane-ethyl acetate to obtain the desired product (3.50 g, yield 78%) as a colorless solid.
  • Reference Example 58 (4) tert-butyl trans-3-hydroxy-3-methyl-1- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl)
  • cyclobutylcarbamate reference example 58 (3) (3.74g) in DMF (42mL)
  • the reaction mixture was cooled to room temperature, diluted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • the obtained residue was purified by silica gel chromatography (hexane: ethyl acetate) to obtain a corresponding coupled product.
  • the obtained coupled product was used for the next reaction without further purification. Hydrazine monohydrate (0.5 mL) was added to an ethanol (2.0 mL) solution of the obtained coupling product, and the mixture was stirred at 110 ° C. for 20 minutes using a microwave reactor.
  • the reaction mixture was cooled to room temperature, diluted with saturated sodium bicarbonate, and extracted with chloroform.
  • the reaction mixture was cooled to room temperature, diluted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • the obtained residue was purified by silica gel chromatography (hexane: ethyl acetate) to obtain a corresponding coupled product.
  • the obtained coupled product was used for the next reaction without further purification.
  • Trifluoroacetic acid 0.5 mL was added to a chloroform (1.0 mL) solution of the obtained coupling product, and the mixture was stirred at room temperature for 1 hour.
  • Example 3 1- (4- (10-Fluoro-3-phenyl-5H-benzo [e] imidazo [1,2-c] [1,3] oxazin-2-yl) phenyl) cyclobutanamine Reference Example 22 (2)
  • the title compound was obtained as a colorless solid by using Reference Example 56 (4) instead of Reference Example 58 (4) in the same manner as in Example 2.
  • Example 4 Trans-3-amino-1-cyclopropyl-3- (4- (10-fluoro-3- (thiophen-3-yl) -5H-benzo [e] imidazo [1,2-c] [1,3] Oxazin-2-yl) phenyl) cyclobutanol
  • Reference Example 30 was obtained in the same manner as in Example 1 to obtain the title compound as a colorless solid.
  • Example 5 Trans-3-Amino-1-cyclopropyl-3- (4- (10-fluoro-3- (pyridin-4-yl) -5H-benzo [e] imidazo [1,2-c] [1,3] Oxazin-2-yl) phenyl) cyclobutanol
  • Reference Example 31 was obtained in the same manner as in Example 1 to obtain the title compound as a colorless solid.
  • Example 6 Trans-3-Amino-3- (4- (10-fluoro-3- (thiophen-3-yl) -5H-benzo [e] imidazo [1,2-c] [1,3] oxazin-2-yl ) Phenyl) -1-methylcyclobutanol
  • Reference Example 30 was obtained in the same manner as in Example 2 to obtain the title compound as a colorless solid.
  • Example 7 Trans-3-Amino-3- (4- (10-fluoro-3- (pyridin-4-yl) -5H-benzo [e] imidazo [1,2-c] [1,3] oxazin-2-yl ) Phenyl) -1-methylcyclobutanol
  • Reference Example 31 was obtained in the same manner as in Example 2 to obtain the title compound as a colorless solid.
  • Example 8 Trans-3-amino-3- (4- (9-fluoro-3-phenyl-5H-benzo [e] imidazo [1,2-c] [1,3] oxazin-2-yl) phenyl) -1- Methylcyclobutanol
  • Reference Example 32 was obtained in the same manner as Example 2, and the title compound was obtained as a colorless solid.
  • Example 9 Trans-3-amino-3- (4- (8-fluoro-3-phenyl-5H-benzo [e] imidazo [1,2-c] [1,3] oxazin-2-yl) phenyl) -1- Methylcyclobutanol Reference Example 33 was obtained in the same manner as Example 2, and the title compound was obtained as a colorless solid.
  • Example 10 Trans-3-Amino-1-cyclopropyl-3- (4- (7-fluoro-3-phenyl-5H-benzo [e] imidazo [1,2-c] [1,3] oxazin-2-yl) Phenyl) cyclobutanol
  • Reference Example 34 was obtained in the same manner as in Example 1 to obtain the title compound as a colorless solid.
  • Example 11 Trans-3-amino-1-cyclopropyl-3- (4- (3-phenyl-5H-benzo [e] imidazo [1,2-c] [1,3] oxazin-2-yl) phenyl) cyclobutanol
  • Reference Example 35 was obtained in the same manner as in Example 1, and the title compound was obtained as a colorless solid.
  • Example 12 Trans-3-Amino-1-methyl-3- (4- (3-phenyl-5H-benzo [e] imidazo [1,2-c] [1,3] oxazin-2-yl) phenyl) cyclobutanol
  • Example 35 was obtained in the same manner as Example 2 to obtain the title compound as a colorless solid.
  • Example 13 1- (4- (3-Phenyl-5H-benzo [e] imidazo [1,2-c] [1,3] oxazin-2-yl) phenyl) cyclobutanamine
  • Reference Example 35 was prepared in the same manner as in Example 2. Thus, the title compound was obtained as a colorless solid by using Reference Example 56 (4) instead of Reference Example 58 (4).
  • Example 14 1- (4- (3- (thiophen-3-yl) -5H-benzo [e] imidazo [1,2-c] [1,3] oxazin-2-yl) phenyl) cyclobutanamine Reference Example 36
  • the title compound was obtained as a colorless solid by using Reference Example 56 (4) instead of Reference Example 58 (4) in the same manner as Example 2.
  • Example 15 1- (4- (3- (pyridin-4-yl) -5H-benzo [e] imidazo [1,2-c] [1,3] oxazin-2-yl) phenyl) cyclobutanamine Reference Example 37
  • the title compound was obtained as a colorless solid by using Reference Example 56 (4) instead of Reference Example 58 (4) in the same manner as Example 2.
  • Example 16 Trans-3-Amino-1-cyclopropyl-3- (4- (10-methoxy-3-phenyl-5H-benzo [e] imidazo [1,2-c] [1,3] oxazin-2-yl) Phenyl) cyclobutanol
  • Reference Example 36 was obtained in the same manner as in Example 1 to obtain the title compound as a colorless solid.
  • Example 17 Trans-3-Amino-1-cyclopropyl-3- (4- (9-methoxy-3-phenyl-5H-benzo [e] imidazo [1,2-c] [1,3] oxazin-2-yl) Phenyl) cyclobutanol Reference Example 39 was obtained in the same manner as in Example 1 to obtain the title compound as a colorless solid.
  • Example 18 Trans-3-amino-1-cyclopropyl-3- (4- (8-methoxy-3-phenyl-5H-benzo [e] imidazo [1,2-c] [1,3] oxazin-2-yl) Phenyl) cyclobutanol
  • Reference Example 40 was obtained in the same manner as in Example 1 to obtain the title compound as a colorless solid.
  • Example 19 Trans-3-amino-1-cyclopropyl-3- (4- (7-methoxy-3-phenyl-5H-benzo [e] imidazo [1,2-c] [1,3] oxazin-2-yl) Phenyl) cyclobutanol
  • Reference Example 41 was obtained in the same manner as in Example 1 to obtain the title compound as a colorless solid.
  • Example 20 Trans-3-amino-3- (4- (9-methoxy-3-phenyl-5H-benzo [e] imidazo [1,2-c] [1,3] oxazin-2-yl) phenyl) -1- Methylcyclobutanol Reference Example 39 was obtained in the same manner as in Example 2 to obtain the title compound as a colorless solid.
  • Example 21 Trans-3-amino-3- (4- (8-methoxy-3-phenyl-5H-benzo [e] imidazo [1,2-c] [1,3] oxazin-2-yl) phenyl) -1- Methylcyclobutanol Reference Example 40 was obtained in the same manner as in Example 2, to obtain the title compound as a colorless solid.
  • Example 22 Lance-3-amino-3- (4- (10-chloro-3-phenyl-5H-benzo [e] imidazo [1,2-c] [1,3] oxazin-2-yl) phenyl) -1- Cyclopropylcyclobutanol Reference Example 42 was obtained in the same manner as in Example 1, to obtain the title compound as a colorless solid.
  • Example 23 Trans-3-Amino-1-cyclopropyl-3- (4- (10-ethoxy-3-phenyl-5H-benzo [e] imidazo [1,2-c] [1,3] oxazin-2-yl) Phenyl) cyclobutanol
  • Reference Example 43 was obtained in the same manner as in Example 1 to obtain the title compound as a colorless solid.
  • Example 24 Trans-3-amino-3- (4- (10-ethoxy-3-phenyl-5H-benzo [e] imidazo [1,2-c] [1,3] oxazin-2-yl) phenyl) -1- Methylcyclobutanol
  • Reference Example 43 was obtained in the same manner as Example 2, and the title compound was obtained as a colorless solid.
  • Example 25 Trans-3-amino-1-cyclopropyl-3- (4- (8,10-dimethoxy-3-phenyl-5H-benzo [e] imidazo [1,2-c] [1,3] oxazine-2- Yl) phenyl) cyclobutanol
  • Reference Example 44 was obtained in the same manner as in Example 1 to obtain the title compound as a colorless solid.
  • Example 26 Trans-3-Amino-1-cyclopropyl-3- (4- (7-methyl-3-phenyl-5H-benzo [e] imidazo [1,2-c] [1,3] oxazin-2-yl) Phenyl) cyclobutanol Reference Example 45 was obtained in the same manner as in Example 1 to obtain the title compound as a colorless solid.
  • Example 27 Trans-3-amino-1-cyclopropyl-3- (4- (3-phenyl-5H-imidazo [1,2-c] pyrido [2,3-e] [1,3] oxazin-2-yl) Phenyl) cyclobutanol
  • Reference Example 46 was obtained in the same manner as in Example 1, to obtain the title compound as a colorless solid.
  • Example 28 Trans-3-Amino-1-methyl-3- (4- (3-phenyl-5H-imidazo [1,2-c] pyrido [2,3-e] [1,3] oxazin-2-yl) phenyl ) Cyclobutanol Reference Example 46 was obtained in the same manner as in Example 2 to obtain the title compound as a colorless solid.
  • Example 29 1- (4- (3-Phenyl-5H-imidazo [1,2-c] pyrido [2,3-e] [1,3] oxazin-2-yl) phenyl) cyclobutanamine Reference Example 46
  • Reference Example 56 (4) was used to obtain the title compound as a colorless solid.
  • Example 30 Trans-3-Amino-1-ethyl-3- (4- (3-phenyl-5H-imidazo [1,2-c] pyrido [2,3-e] [1,3] oxazin-2-yl) phenyl ) Cyclobutanol Reference Example 46 was obtained in the same manner as in Example 2, except that Reference Example 59 was used instead of Reference Example 58 (4) to obtain the title compound as a colorless solid.
  • Example 31 Trans-3-amino-1-cyclopropyl-3- (4- (3-phenyl-5H-imidazo [1,2-c] pyrido [2,3-e] [1,3] oxazin-2-yl) Phenyl) cyclobutanol
  • Reference Example 47 was obtained in the same manner as in Example 1 to obtain the title compound as a colorless solid.
  • Example 32 Trans-3-Amino-1-methyl-3- (4- (3-phenyl-5H-imidazo [1,2-c] pyrido [3,4-e] [1,3] oxazin-2-yl) phenyl ) Cyclobutanol Reference Example 47 was obtained in the same manner as in Example 2 to obtain the title compound as a colorless solid.
  • Example 33 1- (4- (3-Phenyl-5H-imidazo [1,2-c] pyrido [3,4-e] [1,3] oxazin-2-yl) phenyl) cyclobutanamine Reference Example 47
  • Reference Example 56 (4) was used to obtain the title compound as a colorless solid.
  • Example 34 Trans-3-Amino-1-ethyl-3- (4- (3-phenyl-5H-imidazo [1,2-c] pyrido [3,4-e] [1,3] oxazin-2-yl) phenyl ) Cyclobutanol Reference Example 47 was obtained in the same manner as in Example 2, except that Reference Example 59 was used instead of Reference Example 58 (4) to obtain the title compound as a colorless solid.
  • Example 35 Trans-3-amino-1-cyclopropyl-3- (4- (3-phenyl-5H-imidazo [1,2-c] pyrido [4,3-e] [1,3] oxazin-2-yl) Phenyl) cyclobutanol
  • Reference Example 48 was obtained in the same manner as in Example 1 to obtain the title compound as a colorless solid.
  • Example 36 Trans-3-Amino-1-methyl-3- (4- (3-phenyl-5H-imidazo [1,2-c] pyrido [4,3-e] [1,3] oxazin-2-yl) phenyl ) Cyclobutanol Reference Example 48 was obtained in the same manner as in Example 2 to obtain the title compound as a colorless solid.
  • Example 37 1- (4- (3-Phenyl-5H-imidazo [1,2-c] pyrido [4,3-e] [1,3] oxazin-2-yl) phenyl) cyclobutanamine Reference Example 48 In the same manner as in Example 2, instead of Reference Example 58 (4), Reference Example 56 (4) was used to obtain the title compound as a colorless solid.
  • Example 38 Trans-3-amino-1-cyclopropyl-3- (4- (3-phenyl-5H-imidazo [1,2-c] pyrido [3,2-e] [1,3] oxazin-2-yl) Phenyl) cyclobutanol
  • Reference Example 49 was obtained in the same manner as in Example 1 to obtain the title compound as a colorless solid.
  • Example 39 Trans-3-Amino-1-methyl-3- (4- (3-phenyl-5H-imidazo [1,2-c] pyrido [3,2-e] [1,3] oxazin-2-yl) phenyl ) Cyclobutanol Reference Example 49 was obtained in the same manner as in Example 2 to obtain the title compound as a colorless solid.
  • Example 40 1- (4- (3-Phenyl-5H-imidazo [1,2-c] pyrido [3,2-e] [1,3] oxazin-2-yl) phenyl) cyclobutanamine Reference Example 49
  • Reference Example 56 (4) was used to obtain the title compound as a colorless solid.
  • Example 41 Trans-3-Amino-1-cyclopropyl-3- (4- (3-phenyl-5H-imidazo [1,2-c] pyrazo [3,2-e] [1,3] oxazin-2-yl) Phenyl) cyclobutanol
  • Reference Example 50 was obtained in the same manner as in Example 1 to obtain the title compound as a pale yellow solid.
  • Example 42 Trans-3-Amino-1-methyl-3- (4- (3-phenyl-5H-imidazo [1,2-c] pyrazo [3,2-e] [1,3] oxazin-2-yl) phenyl ) Cyclobutanol Reference Example 50 was obtained in the same manner as in Example 2 to obtain the title compound as a pale yellow solid.
  • Example 43 Trans-3-Amino-1-ethyl-3- (4- (3-phenyl-5H-imidazo [1,2-c] pyrazo [3,2-e] [1,3] oxazin-2-yl) phenyl ) Cyclobutanol Reference Example 50 was obtained in the same manner as in Example 2, except that Reference Example 59 was used instead of Reference Example 58 (4) to obtain the title compound as a colorless solid.
  • Example 44 Trans-3-amino-3- (4- (9- (hydroxymethyl) -3-phenyl-5H-benzo [e] imidazo [1,2-c] [1,3] oxazin-2-yl) phenyl)
  • the title compound was obtained as a colorless solid in Reference Example 24 of 1-methylcyclobutanol.
  • Example 45 Trans-3-amino-3- (4- (8- (hydroxymethyl) -3-phenyl-5H-benzo [e] imidazo [1,2-c] [1,3] oxazin-2-yl) phenyl) -1-methylcyclobutanol
  • Reference Example 52 was obtained in the same manner as in Example 2, to obtain the title compound as a colorless solid.
  • Example 46 2- (4- (trans-1-amino-3-hydroxy-3-methylcyclobutyl) phenyl) -3-phenyl-5H-benzo [e] imidazo [1,2-c] [1,3] oxazine- 9-carbonitrile
  • Reference Example 25 was obtained in the same manner as in Example 2, and the title compound was obtained as a colorless solid.
  • Example 47 (4- (trans-1-amino-3-hydroxy-3-methylcyclobutyl) phenyl) -3-phenyl-5H-benzo [e] imidazo [1,2-c] [1,3] oxazine-8 -Carbonitrile Reference Example 53 was obtained in the same manner as in Example 2 to obtain the title compound as a colorless solid.
  • Example 48 Trans-3-Amino-1-methyl-3- (4- (3-phenyl-9- (1H-pyrazol-5-yl) -5H-benzo [e] imidazo [1,2-c] [1,3 ] Oxazin-2-yl) phenyl) cyclobutanol
  • Reference Example 26 was obtained in the same manner as in Example 2 to obtain the title compound as a colorless solid.
  • Example 49 2- (4- (trans-1-amino-3-hydroxy-3-methylcyclobutyl) phenyl) -3-phenyl-5H-benzo [e] imidazo [1,2-c] [1,3] oxazine- 8-Carbonitrile Reference Example 27 was obtained in the same manner as in Example 2, and the title compound was obtained as a colorless solid.
  • Example 50 Trans-3-amino-1-methyl-3- (4- (9-methyl-3-phenyl-5H-imidazo [1,2-c] pyrido [2,3-e] [1,3] oxazine-2 -Il) phenyl) cyclobutanol
  • Reference Example 54 was obtained in the same manner as in Example 2 to obtain the title compound as a colorless solid.
  • Example 51 Trans-3-amino-3- (4- (9-methoxy-3-phenyl-5H-imidazo [1,2-c] pyrido [2,3-e] [1,3] oxazin-2-yl) phenyl ) -1-Methylcyclobutanol
  • Reference Example 55 was obtained in the same manner as in Example 2 to obtain the title compound as a colorless solid.
  • Example 52 (1) Methyl 2- (4- (trans-1- (tert-butoxycarbonylamine) -3-hydroxy-3-methylcyclobutyl) phenyl) -3-phenyl-5H-benzo [e] imidazo [ 1,2-c] [1,3] Oxazine-9-carboxylate Reference Example 23 (4) (148 mg) in 1,4-dioxane (2.4 mL), water (0.4 mL) was added to tert-butyl trans- 3-hydroxy-3-methyl-1- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) cyclobutylcarbamate (125 mg) and cesium carbonate ( 194 mg) was added and the atmosphere was nitrogen, and then Pd (PPh3) 4 (27.5 mg) was added and stirred at 100 ° C.
  • Example 52 (2) 2- (4- (trans-1- (tert-butoxycarbonylamino) -3-hydroxy-3-methylcyclobutyl) phenyl) -3-phenyl-5H-benzo [e] imidazo [1 , 2-c] [1,3] oxazine-9-carboxylic acid
  • 2M aqueous potassium hydroxide 0.6 mL
  • 0.5M aqueous potassium hydrogen sulfate solution was extracted with chloroform.
  • Example 52 (2) (2 mg) in DMF (0.5 mL) was added to methylamine hydrochloride (5.0 mg), triethylamine (0.025 mL), WSC hydrochloride (13.5 mg) and HOBt (10.8 mg) were added, and the mixture was stirred at room temperature for 2 hours and at 90 ° C. for 1 hour. The reaction mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate.
  • Example 53 2- (4- (trans-1-amino-3-hydroxy-3-methylcyclobutyl) phenyl) -3-phenyl-5H-benzo [e] imidazo [1,2-c] [1,3] oxazine- 9-carboxamide
  • 28% aqueous ammonia was used in place of the methylamine hydrochloride of Example 52 (3) to give the title compound as a colorless solid.
  • Example 54 2- (4- (trans-1-amino-3-hydroxy-3-methylcyclobutyl) phenyl) -N, N-dimethyl-3-phenyl-5H-benzo [e] imidazo [1,2-c] [ 1,3] Oxazine-9-carboxamide
  • dimethylamine hydrochloride was used in place of methylamine hydrochloride of Example 52 (3) to give the title compound as a colorless solid.
  • Example 55 2- (4- (trans-1-amino-3-hydroxy-3-methylcyclobutyl) phenyl) -N-ethyl-3-phenyl-5H-benzo [e] imidazo [1,2-c] [1, 3] Oxazine-9-carboxamide
  • ethylamine hydrochloride was used in place of methylamine hydrochloride in Example 52 (3) to give the title compound as a colorless solid.
  • Example 56 2- (4- (trans-1-amino-3-hydroxy-3-methylcyclobutyl) phenyl) -N-methyl-3-phenyl-5H-benzo [e] imidazo [1,2-c] [1, 3] Oxazine-8-carboxamide
  • the title compound was obtained as a colorless solid by reacting Reference Example 51 instead of Reference Example 23 (4).
  • Example 57 2- (4- (trans-1-amino-3-hydroxy-3-methylcyclobutyl) phenyl) -N, N-dimethyl-3-phenyl-5H-benzo [e] imidazo [1,2-c] [ 1,3] Oxazine-8-carboxamide
  • dimethylamine hydrochloride was used, and instead of Reference Example 23 (4).
  • Reference Example 51 By reacting Reference Example 51, the title compound was obtained as a colorless solid.
  • Example 58 2- (4- (trans-1-amino-3-hydroxy-3-methylcyclobutyl) phenyl) -N- (2-hydroxyethyl) -3-phenyl-5H-benzo [e] imidazo [1,2- c] [1,3] oxazine-8-carboxamide
  • 2-aminoethanol was used in place of the methylamine hydrochloride of Example 52 (3), and Reference Example 23 (4 ), By reacting Reference Example 51, The title compound was obtained as a colorless solid.
  • Example 59 2- (4- (trans-1-amino-3-hydroxy-3-methylcyclobutyl) phenyl) -N-ethoxy-3-phenyl-5H-benzo [e] imidazo [1,2-c] [1, 3]
  • Oxazine-8-carboxamide In the same manner as in Example 52, O-ethylhydroxyamine hydrochloride picture salt was used instead of methylamine hydrochloride in Example 52 (3), and Reference Example 23 (4) Instead of reacting Reference Example 51, the title compound was obtained as a colorless solid.
  • Example 60 2- (4- (trans-1-amino-3-hydroxy-3-methylcyclobutyl) phenyl) -N- (2-hydroxyethyl) -3-phenyl-5H-benzo [e] imidazo [1,2- c] [1,3] oxazine-9-carboxamide
  • 2-aminoethanol was used in place of the methylamine hydrochloride of Example 52 (3) to give the title compound as a colorless solid. Obtained.
  • Example 61 2- (4- (trans-1-amino-3-hydroxy-3-methylcyclobutyl) phenyl) -N-ethoxy-3-phenyl-5H-benzo [e] imidazo [1,2-c] [1, 3] Oxazine-9-carboxamide
  • the title compound was obtained as a colorless solid by using O-ethylhydroxyamine hydrochloride instead of methylamine hydrochloride in Example 52 (3). .
  • Example 62 (4- (trans-1-amino-3-hydroxy-3-methylcyclobutyl) phenyl) -3-phenyl-5H-benzo [e] imidazo [1,2-c] [1,3] oxazine-8 -Carboxamide
  • methylamine hydrochloride in Example 52 (3) 28% aqueous ammonia was used, and instead of Reference Example 23 (4), Reference Example 51 was reacted. To give the title compound as a colorless solid.
  • Example 63 2- (4- (trans-1-amino-3-hydroxy-3-methylcyclobutyl) phenyl) -3-phenyl-5H-benzo [e] imidazo [1,2-c] [1,3] oxazine- 9-carboxylic acid hydrochloride
  • ethyl acetate 1.0 mL
  • 4M hydrochloric acid 4M hydrochloric acid in ethyl acetate (0.5 mL)
  • the reaction mixture was filtered, and the residue was washed with ethyl acetate to give the title compound (6.0 mg, yield 35%) as a colorless solid.
  • Example 64 2- (4- (trans-1-amino-3-hydroxy-3-methylcyclobutyl) phenyl) -3-phenyl-5H-benzo [e] imidazo [1,2-c] [1,3] oxazine- 8-Carboxylic acid hydrochloride
  • Reference Example 51 was used to give 2- (4- (trans-1- (tert-butoxycarbonylamino)- 3-Hydroxy-3-methylcyclobutyl) phenyl) -3-phenyl-5H-benzo [e] imidazo [1,2-c] [1,3] oxazine-8-carboxylic acid was obtained.
  • compound-I represents trans-3-amino-1-methyl-3- (4- (3-phenyl-5H-imidazo [1,2-c] pyrido [3 , 4-e] [1,3] oxazin-2-yl) phenyl) cyclobutanol
  • compound-II is trans-3-amino-1-cyclopropyl-3- (4- (3 -Phenyl-5H-imidazo [1,2-c] pyrido [4,3-e] [1,3] oxazin-2-yl) phenyl) cyclobutanol.
  • test solution of paclitaxel (Wako Pure Chemical Industries, Ltd.) alone group was prepared by diluting in 10% ethyl alcohol / 10% cremophor / 80% physiological saline so that the dose of paclitaxel was 60 mg / kg / day.
  • compound-I alone group test solutions were prepared by diluting in 0.5% hydroxypropylmethylcellulose (HPMC) to 8 mg / kg / day, 16 mg / kg / day, and 24 mg / kg / day.
  • HPMC hydroxypropylmethylcellulose
  • Compound-I was orally administered once a day for 14 days from day 1, and paclitaxel was administered from the mouse tail vein on day 1 and day 8.
  • Test Example 2 Antitumor Effect Enhancement Action on Paclitaxel
  • NCI-N87 human gastric cancer strain
  • the test solution of paclitaxel (Wako Pure Chemical Industries, Ltd.) alone group was prepared so that the dose of paclitaxel was 60 mg / kg / day.
  • the test liquid of compound-I single group was prepared so that it might become 8 mg / kg / day, 16 mg / kg / day, and 24 mg / kg / day.
  • Compound-I was orally administered once a day for 14 days from day 1 and paclitaxel was administered from the mouse tail vein on day 1 and day 8.
  • vehicle was administered instead of paclitaxel or compound-I as in Test Example 1.
  • compound-I was administered at 8 mg / kg / day, 16 mg / kg / day, 24 mg / kg / day and paclitaxel at 60 mg / kg / day, and evaluation was performed in the same manner as in Test Example 1. Further, the effect of the combined use was statistically determined in the same manner as in Test Example 1. In the figure and table, * indicates that a statistically significant difference was observed with respect to the single agent group. The results are shown in FIG. The change in body weight over time, which is an index of toxicity, was also evaluated in the same manner as in Test Example 1. The results are shown in FIG.
  • Test Example 3 Antitumor Effect Enhancement Action on Carboplatin
  • a human ovarian cancer strain (A2780) was transplanted subcutaneously into the right side of a 7-week-old female nude rat and used in the same manner as in Test Example 1.
  • Carboplatin was prepared by diluting paraplatin injection (manufactured by Bristol-Myers Squibb, 50 mg / 5 mL) with physiological saline to a dose of 50 mg / kg / day.
  • the compound-I test solution was prepared to be 16 mg / kg / day.
  • Compound-I was orally administered once a day for 14 days from day IV.
  • Carboplatin was administered from mouse tail vein on day 1 and day 8.
  • 0.5% HPMC or physiological saline was administered as a vehicle instead of compound-I or carboplatin, respectively.
  • Test Example 4 Antitumor Effect Enhancement Action on Lapatinib
  • a human gastric cancer strain (NCI-N87) was implanted subcutaneously into the right side of a 7-week-old female BALB / cA Jcl-nu mouse and used in the same manner as in Test Example 1.
  • Lapatinib was prepared to be 100 mg / kg / day.
  • the compound-I test solution was prepared to be 16 mg / kg / day.
  • 0.5% HPMC / 0.1% Tween 80 and 0.5% HPMC were used, respectively.
  • compound-I was 16 mg / kg / day
  • lapatinib was 100 mg / kg / day
  • compound-I was administered at 16 mg / kg / day
  • lapatinib was administered at 100 mg / kg / day, and evaluation was performed in the same manner as in Test Example 1.
  • the effect of the combined use was statistically determined in the same manner as in Test Example 1.
  • * indicates that a statistically significant difference was observed with respect to the single agent group.
  • the results are shown in FIG.
  • the results are shown in FIG.
  • Test Example 5 Antitumor Effect Enhancement Action on Irinotecan
  • a human ovarian cancer strain (A2780) was implanted subcutaneously into the right side of a 7-week-old female BALB / cA Jcl-nu mouse and used in the same manner as in Test Example 1.
  • Irinotecan was prepared by diluting campto infusion (Yakult, 100 mg / 5 mL) with physiological saline to a dose of 75 mg / kg / day.
  • the compound-I test solution was prepared to be 16 mg / kg / day. Saline and 0.5% HPMC were used for irinotecan and compound-I vehicles, respectively.
  • compound-I was orally administered once a day at a dose of 16 mg / kg / day from day 1 to 14 days. Irinotecan was administered at 75 mg / kg / day from day 1 and day 8 via the mouse tail vein.
  • compound-I was administered at 16 mg / kg / day and irinotecan was administered at 75 mg / kg / day, and evaluation was performed in the same manner as in Test Example 1. The effect of the combined use was statistically determined in the same manner as in Test Example 1.
  • * indicates that a statistically significant difference was observed with respect to the single agent group.
  • the results are shown in FIG.
  • Test Example 6 Antitumor Effect Enhancement Action on Doxorubicin A human ovarian cancer strain (A2780) was transplanted subcutaneously into the right side of a 7-week-old female BALB / cA Jcl-nu mouse and used in the same manner as in Test Example 1.
  • the test solution of doxorubicin (adriacin injection, manufactured by Kyowa Hakko Kogyo Co., Ltd.) alone group was prepared by diluting with physiological saline so that the dose of doxorubicin was 7 mg / kg / day.
  • the test solution of compound-I alone group was prepared by diluting with 0.5% HPMC to be 16 mg / kg / day.
  • compound-I was administered at 16 mg / kg / day and doxorubicin at 7 mg / kg / day.
  • Compound-I was orally administered daily for 14 days from day 1 and doxorubicin was orally administered on day 1 and day 8 and evaluated in the same manner as in Test Example 1.
  • the effect of the combined use was statistically determined in the same manner as in Test Example 1.
  • * indicates that a statistically significant difference was observed with respect to the single agent group. The results are shown in FIG.
  • Test Example 7 Effect of enhancing antitumor effect on everolimus
  • a human gastric cancer strain (NCI-N87) was implanted subcutaneously into the right side of a 7-week-old female BALB / cA Jcl-nu mouse and used in the same manner as in Test Example 1.
  • the test solution of Everolimus (IS Chemical) alone group was prepared so that the dose of everolimus was 5 mg / kg / day.
  • the vehicle 5% ethyl alcohol / 5% / 4PEG400 / 4% Tween20 / 86% distilled water was used.
  • the test solution of compound-I alone group was prepared by diluting with 0.5% HPMC so as to be 16 mg / kg / day.
  • compound-I was administered at 16 mg / kg / day and everolimus was administered at 5 mg / kg / day. Both compound-I and everolimus were orally administered once a day for 14 days from day 1 and evaluated in the same manner as in Test Example 1. The results are shown in FIG.
  • Test Example 8 Enhancement of antitumor effect on TS-1 Human gastric cancer strain (4-1ST) was transplanted into the right side of a 6-week-old male BALB / cA Jcl-nu mouse and used in the same manner as in Test Example 1. It was.
  • TS-1 has a molar ratio of FT (Tegafur, manufactured by Taiho Pharmaceutical Co., Ltd.), CDHP (Gimeracil, manufactured by Taiho Pharmaceutical Co., Ltd.) and Oxo (Oteracil potassium, manufactured by Taiho Pharmaceutical Co., Ltd.) in a molar ratio of 1: 0.4: Weighed the one weighed to 1 liter, added a suitable amount of 0.5% (w / v) HPMC aqueous solution so that the FT concentration would be 1.66 mg / mL, and sonicated to make a uniform suspension (A solution of doubling concentration of 8.3 mg / kg / day group).
  • This suspension was diluted 2-fold with 0.5% (w / v) ⁇ HPMC aqueous solution to a concentration of 0.83 mg / mL ⁇ to give a 8.3 mg / kg / day group administration solution.
  • the compound-I test solution was prepared so that compound-I was 16 and 24 mg / kg / day.
  • Compound-I and TS-1 were orally administered once a day for 14 days from day IV1.
  • compound-I was administered at 16 and 24 mg / kg / day
  • TS-1 was administered at 8.3 mg / kg / day
  • evaluation was performed in the same manner as in Test Example 1. The results are shown in FIGS. 15A and 15B and Table 17.
  • Test Example 9 Cancer Cell Growth Inhibitory Effect Enhancement Effect on Bortezomib Human multiple myeloma-derived cell line MM.1S or MM.1R was subcultured and cultured in RPMI-1640 medium containing 10% fetal bovine serum. MM.1S or MM.1R cells were seeded in a 384-well microplate at 1500 cells / 20 ⁇ L / well and cultured overnight in an incubator at 37 ° C., 5% CO 2 , and humidity of 100%. Remove the plate and use compound-II diluted to a final concentration of 7.8, 15.6, 31.3, 62.5, 125, 250, 500, 1000, 2000 nM using RPMI-1640 medium containing DMSO solvent and 10% fetal bovine serum.
  • Test Example 10 Cancer Cell Proliferation Inhibitory Effect Enhancement Effect on Erlotinib
  • Human gastric cancer-derived cell line NCI-N87 was subcultured and cultured in RPMI-1640 medium containing 10% fetal bovine serum.
  • NCI-N87 cells were seeded on a 96-well microplate at 3750 cells / 100 ⁇ L / well, and cultured overnight in an incubator under conditions of 37 ° C., 5% CO 2 and 100% humidity.
  • Compound-II has a final concentration of 0 (DMSO only), 10, 30, 100, 300, 1000, 3000, 10000 nM, and a 200-fold DMSO solution dilution series, and erlotinib has a final concentration of compound-II.
  • a dilution series of 0.1, 0.3, 1, 3, 10 times was prepared. Remove the plate, dilute the dilution series of the above DMSO solution to 4 times the final concentration using RPMI-1640 medium containing 10% fetal bovine serum, and use compound-II and erlotinib as the combination group at all final concentrations. 50 ⁇ L was added per well for each combination. At this time, the total medium volume in the well is 200 ⁇ L. As a control, 100 ⁇ L of DMSO diluted with RPMI-1640 medium containing 10% fetal bovine serum was added to each well. The plate was returned to the incubator and further cultured for 3 days.
  • a combination index (CI) serving as an index of the combined effect was obtained by the same method as in Test Example 9 from the data on the cell growth inhibitory effect obtained by the compound-II single treatment, the erlotinib single treatment and the combined use of both drugs.
  • a CI value of 1.2 or higher was judged to be antagonistic, a value of less than 1.2 and 0.85 or higher was additive, and a CI value of less than 0.85 was considered synergistic.
  • Table 19 below shows the Combination Index. The CI value was 0.25 to 0.52 in the NCI-N87 cell line, and compound-II showed a cytostatic effect synergistic with erlotinib.
  • Test Example 11 Cancer Gas Proliferation Suppressing Effect on Trastuzumab (Herceptin)
  • a human gastric cancer strain (4-1ST) was transplanted subcutaneously into the right side of a 6-week-old male BALB / cA Jcl-nu mouse. Used as in Example 1.
  • Trastuzumab (Roche Pharma) added 7.2 mL of water for injection to a vial containing 150 mg using a sterile syringe according to the package insert, and stored frozen as a 21 mg / mL solution.
  • the test solution for compound-I was prepared to be compound-I 16 and 24 mg / kg / day.
  • Compound-I and trastuzumab were administered once daily from day 1 to 14 days.
  • compound-I was administered at 16 and 24 mg / kg / day
  • trastuzumab was administered at 20 mg / kg / day
  • evaluation was performed in the same manner as in Test Example 1.
  • the results are shown in FIGS. 17A and 17B and Table 20.
  • the vehicle and Compound I groups were orally administered once daily, and trastuzumab was administered intraperitoneally once daily.
  • the effect of the combined use was statistically determined as in Test Example 7.
  • * indicates that a statistically significant difference was observed with respect to the single agent group.
  • the imidazooxazine compound (I) or a pharmaceutically acceptable salt thereof is an antitumor effect of various antitumor agents.
  • the effect was recognized from 8 mg / kg / day which is a low dose of imidazoxazine compound (I) (dose not showing antitumor effect, FIG. 1, Table 11), and a high dose in nude mice (maximum effective dose) 24 mg / kg / day, which was combined, induced significant tumor shrinkage (Tables 11 and 13).
  • the compound of the present invention exhibits an antitumor effect enhancing action without enhancing the toxicity of various antitumor agents.
  • paclitaxel has a difference in antitumor effect (drug sensitivity) depending on the tumor even when the same dose is used, but it is used in combination with the imidazooxazine compound (I).
  • drug sensitivity drug sensitivity
  • the enhancement of the effect is recognized. That is, even in a tumor having low sensitivity to the concomitant drug paclitaxel, it is expected that paclitaxel enhances the tumor growth inhibitory effect by using it in combination with the imidazooxazine compound (I). This means that the combined use of the imidazooxazine compound (I) expands the antitumor spectrum of other antitumor agents.
  • the combined use of imidazooxazine compound (I) or a pharmaceutically acceptable salt thereof and various antitumor agents does not show a marked increase in toxicity, shows an enhanced antitumor effect, and expands the antitumor spectrum.
  • imidazooxazine compound (I) or a pharmaceutically acceptable salt thereof and various antitumor agents does not show a marked increase in toxicity, shows an enhanced antitumor effect, and expands the antitumor spectrum.
  • Test Example 12 Cancer Cell Proliferation Inhibitory Effect Enhancement Effect on Metformin Human ovarian cancer-derived cell line A2780 was subcultured and cultured in RPMI-1640 medium containing 10% fetal bovine serum. A2780 cells were seeded in a 96-well microplate at 2000 cells / 100 ⁇ L / well and cultured overnight in an incubator under conditions of 37 ° C., 5% CO 2 and 100% humidity. Compound-I was adjusted in a 200-fold DMSO solution dilution series so that the final concentration was 0 (DMSO only), 10, 30, 100, 300, 1000, 3000, 10000 nM.
  • Metformin was prepared in RPMI-1640 medium containing 10% fetal calf serum so that the final concentration was 1000, 3333, or 10,000 times that of Compound-I.
  • the plate was removed, and Compound-I and metformin were added to each well as a combination group of Compound-I and metformin as described above for all combinations of final concentrations. At this time, the total medium volume in the well is 200 ⁇ L.
  • 100 ⁇ L of DMSO diluted to a final concentration of 0.5% using RPMI-1640 medium containing 10% fetal bovine serum was added to each well. The plate was returned to the incubator and further cultured for 3 days.
  • Combination Index which is an index of the combined effect, was obtained by the same method as in Test Example 9 from the data on the cell growth inhibitory effect obtained by Compound-I single treatment, erlotinib single treatment and the combined use of both drugs.
  • a CI value of 1.2 or higher was judged to be antagonistic, a value of less than 1.2 and 0.85 or higher was additive, and a CI value of less than 0.85 was considered synergistic.
  • the following table shows the Combination Index.
  • the CI value was 0.08 to 0.96 in the A2780 cell line, and Compound-I exhibited an additive or synergistic cell growth inhibitory effect with metformin.
  • Test Example 13 Cancer Cell Growth Inhibitory Effect Enhancement Action on Docetaxel Human ovarian cancer-derived cell line A2780 was subcultured and cultured in RPMI-1640 medium containing 10% fetal bovine serum. A2780 cells were seeded on a 96-well microplate at 2000 cells / 150 ⁇ L / well and cultured overnight in an incubator under conditions of 37 ° C., 5% CO 2 and 100% humidity. Compound-I was prepared in a 200-fold DMSO solution dilution series so that the final concentrations were 0 (DMSO only), 10, 30, 100, 300, 1000, 3000, and 10000 nM.
  • Docetaxel was prepared in RPMI-1640 medium containing 10% fetal bovine serum so that the final concentration was 0.01, 0.03 times that of Compound-I.
  • the plate was removed, and Compound-I and docetaxel were added to each well as a combination group of Compound-I and docetaxel as described above to obtain all combinations of final concentrations.
  • the total medium volume in the well is 200 ⁇ L.
  • 50 ⁇ L of DMSO diluted to a final concentration of 0.5% using RPMI-1640 medium containing 10% fetal bovine serum was added to each well.
  • the plate was returned to the incubator and further cultured for 3 days.
  • a combination index (CI) serving as an index of the combined effect was obtained in the same manner as in Test Example 9.
  • a CI value of 1.2 or higher was judged to be antagonistic, a value of less than 1.2 and 0.85 or higher was additive, and a CI value of less than 0.85 was considered synergistic.
  • the following table shows the Combination Index. The CI value was 0.33 to 0.67 in the A2780 cell line, and Compound-I showed an additive or synergistic cell growth inhibitory effect with docetaxel.

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EP13813275.8A EP2868660B1 (en) 2012-07-02 2013-07-01 Antitumor effect potentiator comprising an imidazooxazine compound
RU2015103151A RU2618423C2 (ru) 2012-07-02 2013-07-01 Усилитель противоопухолевого эффекта, содержащий имидазооксазиновое соединение
KR1020167030063A KR20160128456A (ko) 2012-07-02 2013-07-01 이미다조옥사진 화합물에 의한 항종양 효과 증강제
DK13813275.8T DK2868660T3 (da) 2012-07-02 2013-07-01 Anti-tumoreffekt-potentiator omfattende en imidazooxazin-forbindelse
ES13813275.8T ES2660215T3 (es) 2012-07-02 2013-07-01 Potenciador de efecto antitumoral que comprende un compuesto de imidazooxazina
PL13813275T PL2868660T3 (pl) 2012-07-02 2013-07-01 Środek wzmacniający działanie przeciwnowotworowe zawierający związek imidazooksazynowy
AU2013284570A AU2013284570B2 (en) 2012-07-02 2013-07-01 Antitumor effect potentiator composed of imidazooxazine compound
KR1020157001880A KR101671761B1 (ko) 2012-07-02 2013-07-01 이미다조옥사진 화합물에 의한 항종양 효과 증강제
JP2014523736A JP5855250B2 (ja) 2012-07-02 2013-07-01 イミダゾオキサジン化合物による抗腫瘍効果増強剤
US14/407,745 US9375434B2 (en) 2012-07-02 2013-07-01 Antitumor effect potentiator composed of imidazooxazine compound
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US10835536B2 (en) 2013-07-18 2020-11-17 Taiho Pharmaceutical Co., Ltd. Therapeutic agent for FGFR inhibitor-resistant cancer
JPWO2020256096A1 (https=) * 2019-06-21 2020-12-24
US10894048B2 (en) 2013-07-18 2021-01-19 Taiho Pharmaceutical Co., Ltd. Antitumor drug for intermittent administration of FGFR inhibitor
WO2021219513A1 (en) 2020-04-28 2021-11-04 Basf Se Pesticidal compounds
US11833151B2 (en) 2018-03-19 2023-12-05 Taiho Pharmaceutical Co., Ltd. Pharmaceutical composition including sodium alkyl sulfate
US11883404B2 (en) 2016-03-04 2024-01-30 Taiho Pharmaceuticals Co., Ltd. Preparation and composition for treatment of malignant tumors
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EP4284378A4 (en) * 2021-02-01 2024-12-25 Taiho Pharmaceutical Co., Ltd. Ptentreating cancer in patient with pten inactivating mutation
CN118302417A (zh) * 2021-08-25 2024-07-05 Ptc医疗公司 Nlrp3抑制剂
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Publication number Priority date Publication date Assignee Title
US10835536B2 (en) 2013-07-18 2020-11-17 Taiho Pharmaceutical Co., Ltd. Therapeutic agent for FGFR inhibitor-resistant cancer
US10894048B2 (en) 2013-07-18 2021-01-19 Taiho Pharmaceutical Co., Ltd. Antitumor drug for intermittent administration of FGFR inhibitor
CN111943962A (zh) * 2015-02-27 2020-11-17 大鹏药品工业株式会社 咪唑并噁嗪晶体、含有所述晶体的药物组合物和制备所述晶体的方法
US11883404B2 (en) 2016-03-04 2024-01-30 Taiho Pharmaceuticals Co., Ltd. Preparation and composition for treatment of malignant tumors
US11975002B2 (en) 2016-03-04 2024-05-07 Taiho Pharmaceutical Co., Ltd. Preparation and composition for treatment of malignant tumors
US11833151B2 (en) 2018-03-19 2023-12-05 Taiho Pharmaceutical Co., Ltd. Pharmaceutical composition including sodium alkyl sulfate
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US9375434B2 (en) 2016-06-28
HUE036188T2 (hu) 2018-06-28
EP2868660A1 (en) 2015-05-06
KR20160128456A (ko) 2016-11-07
KR101671761B1 (ko) 2016-11-02
TW201408671A (zh) 2014-03-01
PT2868660T (pt) 2018-02-02
EP2868660A4 (en) 2016-03-23
AU2013284570B2 (en) 2016-04-14
PL2868660T3 (pl) 2018-05-30
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JP5855250B2 (ja) 2016-02-09
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