JP2021528370A - 重水素化デファクチニブ化合物及びその使用 - Google Patents
重水素化デファクチニブ化合物及びその使用 Download PDFInfo
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- JP2021528370A JP2021528370A JP2020562682A JP2020562682A JP2021528370A JP 2021528370 A JP2021528370 A JP 2021528370A JP 2020562682 A JP2020562682 A JP 2020562682A JP 2020562682 A JP2020562682 A JP 2020562682A JP 2021528370 A JP2021528370 A JP 2021528370A
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- pharmaceutically acceptable
- acceptable salt
- hydrate
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- ABRVLXLNVJHDRQ-UHFFFAOYSA-N [2-pyridin-3-yl-6-(trifluoromethyl)pyridin-4-yl]methanamine Chemical compound FC(C1=CC(=CC(=N1)C=1C=NC=CC=1)CN)(F)F ABRVLXLNVJHDRQ-UHFFFAOYSA-N 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- VREFGVBLTWBCJP-UHFFFAOYSA-N alprazolam Chemical compound C12=CC(Cl)=CC=C2N2C(C)=NN=C2CN=C1C1=CC=CC=C1 VREFGVBLTWBCJP-UHFFFAOYSA-N 0.000 description 1
- 229960004538 alprazolam Drugs 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 1
- 229910000024 caesium carbonate Inorganic materials 0.000 description 1
- 229960001948 caffeine Drugs 0.000 description 1
- VJEONQKOZGKCAK-UHFFFAOYSA-N caffeine Natural products CN1C(=O)N(C)C(=O)C2=C1C=CN2C VJEONQKOZGKCAK-UHFFFAOYSA-N 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- 238000007405 data analysis Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 230000035622 drinking Effects 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 238000007876 drug discovery Methods 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 150000004675 formic acid derivatives Chemical class 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 238000003304 gavage Methods 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 230000005484 gravity Effects 0.000 description 1
- 229960002897 heparin Drugs 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- 210000003494 hepatocyte Anatomy 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- DKYWVDODHFEZIM-UHFFFAOYSA-N ketoprofen Chemical compound OC(=O)C(C)C1=CC=CC(C(=O)C=2C=CC=CC=2)=C1 DKYWVDODHFEZIM-UHFFFAOYSA-N 0.000 description 1
- 229960000991 ketoprofen Drugs 0.000 description 1
- 229960001632 labetalol Drugs 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 238000012417 linear regression Methods 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 238000006241 metabolic reaction Methods 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- IETKYMZYQKEXLW-UHFFFAOYSA-N n-[3-(aminomethyl)pyrazin-2-yl]-n-methylmethanesulfonamide Chemical compound CS(=O)(=O)N(C)C1=NC=CN=C1CN IETKYMZYQKEXLW-UHFFFAOYSA-N 0.000 description 1
- 150000002823 nitrates Chemical class 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- OXNIZHLAWKMVMX-UHFFFAOYSA-N picric acid Chemical compound OC1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-N 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-M toluenesulfonate group Chemical group C=1(C(=CC=CC1)S(=O)(=O)[O-])C LBLYYCQCTBFVLH-UHFFFAOYSA-M 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 238000002604 ultrasonography Methods 0.000 description 1
- 229960001722 verapamil Drugs 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/05—Isotopically modified compounds, e.g. labelled
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
Description
R1〜R18は、それぞれ独立して、水素、重水素から選択され、且つ全てが水素ではない。
第1ステップ:母液を以下の表1の成分比で調製した。
1)実験材料及び測定機器
LC−20AD高速液体クロマトグラフシステム、日本SHIMADZU(島津)社から購入
API4000トリプル四重極型質量分析計、アメリカApplied Biosystem社から購入
PhenixWinnolin薬物動態ソフトウェア(Version6.3)、米Certara社から購入
高速冷凍遠心機、Thermo Fisher Scientificから購入
分析天秤、ザルトリウスから購入、SECURA225D−1CN
SDラット、成都達碩実験動物有限会社から購入
N,N−ジメチルアセトアミド(DMA)(Sigma)
カルボキシメチルセルロースナトリウム(CMC−Na)及びヘパリン、成都科龍化工社から購入
2)実験方法及び結果
適量の薬物(プロトタイプ薬10mgに相当)を精密に秤取し、DMA0.25mlを加えて溶解させた後、0.5%のCMC−Naを5mlまでゆっくりと加え、超音波及びボルテックスにより均一に混合した。調製した最終溶液を0.2ml取り、−20℃で保存し、濃度測定に用いた。健康な成獣の雄のSDラット3匹(180〜250g)を一晩絶食させた(飲水は自由)後に、強制経口により薬物を投与した。投与体積は5ml/kgとした。投与前、及び投与後0.5、1、2、4、6、8、12、24hにおいて、眼窩後静脈叢から0.1ml採血し、4℃で5min遠心機にかけて血漿を分離させ、−20℃で保存し測定に備えた。次いで、LC/MS/MS法により血漿中の測定対象化合物の濃度を測定した。
Claims (11)
- 前記薬学的に許容可能な塩が、前記化合物のリン酸塩、右旋性カンファースルホン酸塩、塩酸塩、臭化水素酸塩、フッ化水素酸塩、硫酸塩、硝酸塩、ギ酸塩、酢酸塩、プロピオン酸塩、シュウ酸塩、マロン酸塩、コハク酸塩、フマル酸塩、マレイン酸塩、乳酸塩、リンゴ酸塩、酒石酸塩、クエン酸塩、ピクリン酸塩、メタンスルホン酸塩、トルエンスルホン酸塩、ベンゼンスルホン酸塩、アスパラギン酸塩又はグルタミン酸塩であり、好ましくは塩酸塩であることを特徴とする、請求項1から6のいずれか1項に記載の化合物、又はその光学異性体、薬学的に許容可能な塩、水和物もしくは溶媒和物。
- 請求項1から7のいずれか1項に記載の化合物、又はその光学異性体、薬学的に許容可能な塩、水和物もしくは溶媒和物の、癌治療の薬物の製造における使用。
- 前記癌が膵臓癌、固形腫瘍、非小細胞肺癌、中皮腫、卵巣癌から選択されることを特徴とする、請求項8に記載の使用。
- 請求項1から7のいずれか1項に記載の化合物、又はその光学異性体、薬学的に許容可能な塩、水和物もしくは溶媒和物の、FAK阻害剤の製造における使用。
- 癌治療の薬物であって、請求項1から7のいずれか1項に記載の化合物、又はその光学異性体、薬学的に許容可能な塩、水和物もしくは溶媒和物を活性成分とし、薬学的に許容可能な補助材料を加えて製造される製剤であることを特徴とする、癌治療の薬物。
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JP2010524914A (ja) * | 2007-04-18 | 2010-07-22 | ファイザー・プロダクツ・インク | 異常細胞増殖治療のためのスルホニルアミド誘導体 |
US20110053968A1 (en) * | 2009-06-09 | 2011-03-03 | Auspex Pharmaceuticals, Inc. | Aminopyrimidine inhibitors of tyrosine kinase |
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WO2010144499A2 (en) * | 2009-06-09 | 2010-12-16 | Medolution Limited | Urea derivatives as kinase inhibitors |
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US20110053968A1 (en) * | 2009-06-09 | 2011-03-03 | Auspex Pharmaceuticals, Inc. | Aminopyrimidine inhibitors of tyrosine kinase |
Non-Patent Citations (1)
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JONES, SF ET AL.: "A Phase I study of VS-6063, a second-generation focal adhesion kinase inhibitor, in patients with ad", INVESTIGATIONAL NEW DRUGS, vol. 33, JPN6022013601, 2015, pages 1100 - 1107, XP035547426, ISSN: 0004748987, DOI: 10.1007/s10637-015-0282-y * |
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US11891379B2 (en) | 2024-02-06 |
JP2023078389A (ja) | 2023-06-06 |
CA3099771A1 (en) | 2019-11-14 |
KR20210006956A (ko) | 2021-01-19 |
CA3099771C (en) | 2024-04-30 |
EP3792257A1 (en) | 2021-03-17 |
KR102632257B1 (ko) | 2024-01-31 |
CN110452229B (zh) | 2020-11-27 |
WO2019214587A1 (zh) | 2019-11-14 |
US20210238166A1 (en) | 2021-08-05 |
CN110452229A (zh) | 2019-11-15 |
EP3792257A4 (en) | 2022-01-19 |
AU2019266718A1 (en) | 2021-01-07 |
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