JP6791338B2 - ジヒドロインドリジノン誘導体 - Google Patents
ジヒドロインドリジノン誘導体 Download PDFInfo
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- JP6791338B2 JP6791338B2 JP2019194671A JP2019194671A JP6791338B2 JP 6791338 B2 JP6791338 B2 JP 6791338B2 JP 2019194671 A JP2019194671 A JP 2019194671A JP 2019194671 A JP2019194671 A JP 2019194671A JP 6791338 B2 JP6791338 B2 JP 6791338B2
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- ethyl acetate
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- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 229940012831 stearyl alcohol Drugs 0.000 description 1
- 210000004500 stellate cell Anatomy 0.000 description 1
- 239000006190 sub-lingual tablet Substances 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- MBGGBVCUIVRRBF-UHFFFAOYSA-N sulfinpyrazone Chemical compound O=C1N(C=2C=CC=CC=2)N(C=2C=CC=CC=2)C(=O)C1CCS(=O)C1=CC=CC=C1 MBGGBVCUIVRRBF-UHFFFAOYSA-N 0.000 description 1
- 229960003329 sulfinpyrazone Drugs 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 150000003892 tartrate salts Chemical class 0.000 description 1
- MNEQGZINEZEYDO-UHFFFAOYSA-N tert-butyl n-[4-(2-bromoacetyl)phenyl]carbamate Chemical compound CC(C)(C)OC(=O)NC1=CC=C(C(=O)CBr)C=C1 MNEQGZINEZEYDO-UHFFFAOYSA-N 0.000 description 1
- TUNFSRHWOTWDNC-HKGQFRNVSA-N tetradecanoic acid Chemical compound CCCCCCCCCCCCC[14C](O)=O TUNFSRHWOTWDNC-HKGQFRNVSA-N 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- QEMXHQIAXOOASZ-UHFFFAOYSA-N tetramethylammonium Chemical compound C[N+](C)(C)C QEMXHQIAXOOASZ-UHFFFAOYSA-N 0.000 description 1
- OULAJFUGPPVRBK-UHFFFAOYSA-N tetratriacontyl alcohol Natural products CCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCO OULAJFUGPPVRBK-UHFFFAOYSA-N 0.000 description 1
- 239000003868 thrombin inhibitor Substances 0.000 description 1
- 230000002537 thrombolytic effect Effects 0.000 description 1
- 239000003768 thromboxane synthase inhibitor Substances 0.000 description 1
- 210000001685 thyroid gland Anatomy 0.000 description 1
- OEKWJQXRCDYSHL-FNOIDJSQSA-N ticagrelor Chemical compound C1([C@@H]2C[C@H]2NC=2N=C(N=C3N([C@H]4[C@@H]([C@H](O)[C@@H](OCCO)C4)O)N=NC3=2)SCCC)=CC=C(F)C(F)=C1 OEKWJQXRCDYSHL-FNOIDJSQSA-N 0.000 description 1
- 229960002528 ticagrelor Drugs 0.000 description 1
- 230000036962 time dependent Effects 0.000 description 1
- 229960005062 tinzaparin Drugs 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-M toluenesulfonate group Chemical class C=1(C(=CC=CC1)S(=O)(=O)[O-])C LBLYYCQCTBFVLH-UHFFFAOYSA-M 0.000 description 1
- 238000011883 total knee arthroplasty Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- 230000009261 transgenic effect Effects 0.000 description 1
- 201000010875 transient cerebral ischemia Diseases 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- ODLHGICHYURWBS-LKONHMLTSA-N trappsol cyclo Chemical compound CC(O)COC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)COCC(O)C)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1COCC(C)O ODLHGICHYURWBS-LKONHMLTSA-N 0.000 description 1
- 230000008733 trauma Effects 0.000 description 1
- 208000018726 traumatic encephalopathy Diseases 0.000 description 1
- SEDZOYHHAIAQIW-UHFFFAOYSA-N trimethylsilyl azide Chemical compound C[Si](C)(C)N=[N+]=[N-] SEDZOYHHAIAQIW-UHFFFAOYSA-N 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical class OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 238000004704 ultra performance liquid chromatography Methods 0.000 description 1
- 229960005356 urokinase Drugs 0.000 description 1
- 230000008728 vascular permeability Effects 0.000 description 1
- 229940099259 vaseline Drugs 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- PJVWKTKQMONHTI-UHFFFAOYSA-N warfarin Chemical compound OC=1C2=CC=CC=C2OC(=O)C=1C(CC(=O)C)C1=CC=CC=C1 PJVWKTKQMONHTI-UHFFFAOYSA-N 0.000 description 1
- 229960005080 warfarin Drugs 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 239000003871 white petrolatum Substances 0.000 description 1
Images
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
-
- 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
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Description
[1]一般式(I)
XはCHまたはNを表す。]
で示される化合物、その塩、その溶媒和物、そのN−オキシド体またはそのプロドラッグ、
[2]一般式(I)で示される化合物が、(3S)−3−[5−(6−アミノ−2−フルオロ−3−ピリジニル)−4−フルオロ−1H−イミダゾール−2−イル]−7−[5−クロロ−2−(1H−テトラゾール−1−イル)フェニル]−2,3−ジヒドロ−5(1H)−インドリジノンである前記[1]記載の化合物、その塩、その溶媒和物、そのN−オキシド体またはそのプロドラッグ、
[3]一般式(I)で示される化合物が、(3S)−3−[2−(6−アミノ−2−フルオロ−3−ピリジニル)−4−フルオロ−1H−イミダゾール−5−イル]−7−[5−クロロ−2−(1H−テトラゾール−1−イル)フェニル]−2,3−ジヒドロ−5(1H)−インドリジノンである前記[1]記載の化合物、その塩、その溶媒和物、そのN−オキシド体またはそのプロドラッグ、
[4]一般式(I)で示される化合物が、(6S)−6−[2−(6−アミノ−2−フルオロ−3−ピリジニル)−4−フルオロ−1H−イミダゾール−5−イル]−2−[5−クロロ−2−(1H−テトラゾール−1−イル)フェニル]−7,8−ジヒドロピロロ[1,2−a]ピリミジン−4(6H)−オンである前記[1]記載の化合物、その塩、その溶媒和物、そのN−オキシド体またはそのプロドラッグ、
[5]一般式(I)で示される化合物が、1−(2−{(3S)−3−[5−(4−アミノフェニル)−4−フルオロ−1H−イミダゾール−2−イル]−5−オキソ−1,2,3,5−テトラヒドロ−7−インドリジニル}−4−クロロフェニル)−1H−1,2,3−トリアゾール−4−カルボニトリルである前記[1]記載の化合物、その塩、その溶媒和物、そのN−オキシド体またはそのプロドラッグ、
[6]前記[1]〜[5]のいずれか1つに記載の化合物、その塩、その溶媒和物、そのN−オキシド体またはそのプロドラッグを有効成分として含有する医薬組成物、
[7]前記[1]〜[5]のいずれか1つに記載の化合物、その塩、その溶媒和物、そのN−オキシド体またはそのプロドラッグを有効成分として含有するFXIa阻害剤、
[8]前記[1]〜[5]のいずれか1つに記載の化合物、その塩、その溶媒和物、そのN−オキシド体またはそのプロドラッグを有効成分として含有する血栓塞栓性疾患の予防および/または治療剤、
[9]血栓塞栓性疾患が、動脈性心血管血栓塞栓性障害、静脈性心血管血栓塞栓性障害、動脈性脳血管血栓塞栓性障害、静脈性脳血管血栓塞栓性障害、または心腔もしくは末梢循環における血栓塞栓性障害である前記[8]に記載の剤、
[10]血栓塞栓性疾患が、冠動脈疾患、不安定狭心症、急性冠症候群、心房細動、心筋梗塞、虚血性突然死、一過性脳虚血発作、脳卒中、末梢動脈疾患、アテローム性動脈硬化症、末梢閉塞性動脈疾患、静脈血栓症、静脈血栓塞栓症、深部静脈血栓症、血栓性静脈炎、動脈塞栓症、冠状動脈血栓症、大脳動脈血栓症、脳塞栓症、腎臓塞栓症、門脈血栓症、肺塞栓症、肺梗塞、肝塞栓症、肝中心静脈閉塞症/類洞閉塞症候群、血栓性微小血管障害症、播種性血管内凝固症候群、敗血症、急性呼吸窮迫症候群、急性肺損傷、抗リン脂質抗体症候群、冠動脈バイパス移植手術に起因する血栓症または血栓形成を促進する人工物表面に血液が曝露される治療により引き起こされる血栓症である、前記[8]または[9]のいずれか1つに記載の剤、
[11]血栓塞栓性疾患が、静脈血栓塞栓症、虚血性脳卒中、血栓形成を促進する人工物表面に血液が暴露される治療により引き起こされる血栓塞栓性疾患、急性冠症候群、冠動脈疾患または末梢動脈疾患である、前記[8]〜[10]のいずれかに記載の剤、
[12]血栓塞栓性疾患を予防および/または治療するための前記[1]〜[5]のいずれか1つに記載の化合物、その塩、その溶媒和物、そのN−オキシド体またはそのプロドラッグ、
[13]血栓塞栓性疾患の予防および/または治療剤を製造するための前記[1]〜[5]のいずれか1つに記載の化合物、その塩、その溶媒和物、そのN−オキシド体またはそのプロドラッグの使用、および
[14]血栓塞栓性疾患の予防および/または治療が必要な患者に有効投与量の前記[1]〜[5]のいずれか1つに記載の化合物、その塩、その溶媒和物、そのN−オキシド体またはそのプロドラッグを投与することからなる該疾患の予防および/または治療方法等に関する。
本発明化合物は、公知の方法、例えば、以下に示す方法、実施例に記載した方法あるいは、Comprehensive Organic Transformations:A Guide to Functional Group Preparations 2nd Edition(Richard C. Larock, John Wiley & Sons Inc, 1999に記載された方法等を適宜改良し、組み合わせて用いることで製造することができる。
本発明化合物の毒性は十分に低いものであり、医薬品として安全に使用することができる。
本発明化合物は、強力なFXIa阻害活性を有する。したがって、本発明化合物は血栓塞栓性疾患、例えば、動脈性心血管血栓塞栓性障害、静脈性心血管血栓塞栓性障害、動脈性脳血管血栓塞栓性障害、静脈性脳血管血栓塞栓性障害、および心腔または末梢循環における血栓塞栓性障害の予防および/または治療に有用である。
(1)その予防、治療および/または症状改善効果の補完および/または増強、
(2)その動態・吸収改善、投与量の低減、および/または
(3)その副作用の軽減のために、他の有効成分、例えば、以下に列挙するような薬剤等と組み合わせ、併用剤として用いてもよい。
条件a.カラムYMC−Triart C18、2.0mmx30mm、1.9μm;カラム温度30℃;移動相(A液)0.1%トリフルオロ酢酸水溶液および(B液)0.1%トリフルオロ酢酸アセトニトリル溶液;流速1.0mL/min;分析時間1.5分;グラジエント:0分(A液/B液=95/5)、0.1分(A液/B液=95/5)、1.2分(A液/B液=5/95)、1.4分(A液/B液=5/95)、1.41分(A液/B液=95/5),1.5分(A液/B液=95/5)
条件b.カラムWaters ACQUITY UPLC(登録商標) BEH C18、 2.1mm x 30mm、 1.7 μm;カラム温度40℃;移動相(A液)0.1%ギ酸水溶液および(B液)0.1%ギ酸アセトニトリル溶液;流速1.0mL/min;分析時間1.5分;グラジエント:0分(A液/B液=95/5)、0.1分(A液/B液=95/5)、1.2分(A液/B液=5/95)、1.4分(A液/B液=5/95)、1.41分(A液/B液=95/5),1.5分(A液/B液=95/5)
実施例1(1):2−メチル−2−プロパニル (6−フルオロ−5−ヨード−2−ピリジニル)カルバマート
6−フルオロ−5−ヨードピリジン−2−アミン(17g)のアセトニトリル(150mL)溶液にジ−tert−ブチルジカーボネート(17.14g)および4−ジメチルアミノピリジン(0.87g)を加え、混合物を室温にて2時間撹拌した。さらにジ−tert−ブチルジカーボネート(7.8g)を加え、室温にてさらに2時間撹拌した。反応混合物に、飽和塩化アンモニウム水溶液と酢酸エチルを加え、不溶物を除去した。併せた有機層を飽和食塩水で洗浄し、乾燥後、濃縮した。残渣を2回のカラムクロマトグラフィー(酢酸エチル:ヘキサン=0:100→25:75)、(アミノシリカ、酢酸エチル:ヘキサン=10:90→50:50にて精製し、以下の物性値を有する標題化合物(9.2g)を得た。
TLC:Rf 0.69(酢酸エチル:ヘキサン=25:75)。
実施例1(1)で製造した化合物(40g)のN,N−ジメチルホルムアミド溶液(200mL)にトリブチル(1−エトキシエテニル)すず(50g)を加えた。混合物をアルゴンで脱気し、テトラキス(トリフェニルホスフィン)パラジウム(0)(3.24g)を加え、混合物を100℃で16時間撹拌した。反応混合物を酢酸エチル(200mL)で希釈し、1Mフッ化カリウム水溶液(500mL)に注いだ。混合物を30分撹拌した後、セライト(登録商標)を通して濾過し、ろ液を酢酸エチルで抽出した。併せた有機層を水および飽和食塩水で洗浄し、乾燥後濃縮した。残渣をカラムクロマトグラフィー(アミノシリカ、酢酸エチル:ヘキサン=3:97→5:95)にて精製し、以下の物性値を有する標題化合物(34.4g)を得た。
LC/MS tR 1.15 分: MS (ES+) m/z 227 [M-CH2C(CH3)2)+H] (条件a)。
実施例1(2)で製造した化合物(34.4g)をテトラヒドロフラン(150mL)と水(50mL)に溶解し、氷冷下N−ブロモコハク酸イミド(21.7g)を加えた。混合物を氷冷下30分撹拌した後、酢酸エチルで希釈し、飽和炭酸水素ナトリウム水溶液で2回洗浄した。有機層を飽和食塩水で洗浄し、乾燥後濃縮した。残渣をカラムクロマトグラフィー(酢酸エチル:ヘキサン=10:90→30:70)にて精製し、以下の物性値を有する標題化合物(27.58g)を得た。
TLC:Rf 0.26(酢酸エチル:ヘキサン=10:90)。
(3S)−7−[5−クロロ−2−(1H−1,2,3,4−テトラゾール−1−イル)フェニル]−5−オキソ−1,2,3,5−テトラヒドロインドリジン−3−カルボン酸(特許文献6の実施例9に記載)(27.58g)と実施例1(3)で製造した化合物(25.68g)のN−メチルピロリドン溶液(200mL)に氷冷下N,N−ジイソプロピルエチルアミン(26.7mL)を加えた。室温にて30分撹拌した後、反応混合物を酢酸エチル(200mL)で希釈し飽和塩化アンモニウム水溶液(500mL)で洗浄した。水層を酢酸エチルで抽出し、合わせた有機層を水(500mL)、飽和食塩水(500mL)で洗浄し、乾燥後濃縮した。残渣をトルエン(500mL)と氷酢酸(50mL)に溶解し、酢酸アンモニウム(59.4g)を加え、混合物を100℃で3時間撹拌した。混合物を減圧濃縮し、酢酸エチルで希釈し、飽和炭酸カリウム水溶液(500mL)にて洗浄した。水層を酢酸エチルで抽出し、合わせた有機層を乾燥後濃縮した。残渣をカラムクロマトグラフィー(酢酸エチル:ヘキサン=50:50→100:0)にて精製し、以下の物性値を有する標題化合物(33.5g)を得た。
LC/MS tR 0.84分: MS (ES+) m/z 590 (M+H) (条件a)。
実施例1(4)で製造した化合物(350mg)をテトラヒドロフラン(1.2mL)とアセトニトリル(3.6mL)に溶解し、ピリジン(0.14mL)を加え、−18oCにて1−クロロメチル−4−フルオロ−1,4−ジアゾニアビシクロ[2.2.2]オクタン ビス(テトラフルオロボラート)(315mg)を加え、2時間撹拌した。反応混合物を酢酸エチルで希釈し、亜硫酸ナトリウム水溶液を加え撹拌した。水を加え分液し、水層を酢酸エチルで抽出した。有機層を合わせ、塩酸、飽和炭酸水素ナトリウム水溶液、飽和食塩水で洗浄し、乾燥後濃縮した。残渣をカラムクロマトグラフィー(酢酸エチル:ヘキサン=30:70→100:0)にて精製し、以下の物性値を有する標題化合物(138mg)を得た。
TLC:Rf 0.51(酢酸エチル:ヘキサン=80:20)。
TLC:Rf 0.48(酢酸エチル);
1H-NMR (CD3OD): δ 9.34 (s, 1H), 7.76 - 7.62 (m, 4H), 6.45 (dd, 1H), 6.13 (s, 1H), 6.07 (s, 1H), 5.71 (d, 1H), 3.42 (m, 1H), 3.06 (m, 1H), 2.58 (m, 1H), 2.42 (m, 1H)。
N−ヨードスクシンイミド(56.5g)を氷冷下、6−フルオロ−2−ピリジナミン(25.6g)のN,N−ジメチルホルムアミド(200mL)溶液に分割投入(3回)した。室温で3時間撹拌した後、反応液に市水(0.5L)を加えた。酢酸エチル/ヘキサン(1/1、300mL)で3回抽出し、有機層を飽和亜硫酸水溶液(0.5L)、飽和炭酸ナトリウム水溶液(0.5L、2回)、市水(0.5L)、飽和食塩水(0.5L)で洗浄し、乾燥後、濃縮した。得られた残渣にヘキサン/酢酸エチル(3/1、150mL)を加え、室温下スラリー洗浄し、ろ過した。得られた固体を乾燥し、以下の物性値を有する標題化合物(36.7g)を得た。
TLC:Rf 0.56(酢酸エチル:ヘキサン=1:2)。
実施例2(1)で製造した化合物(36.7g)と4−ジメチルアミノピリジン(0.9g)のアセトニトリル(300mL)溶液にジ−tert−ブチルジカーボネート(74.0g)のアセトニトリル(100mL)溶液を加え、室温で3時間撹拌した。反応溶液を濃縮し、得られた残渣を酢酸エチル(500mL)に溶解し、飽和塩化アンモニウム水溶液(400mL)で洗浄し、水層を酢酸エチル(200mL)で抽出した。合わせた有機層を乾燥後、濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィーにより精製(酢酸エチル:ヘキサン=5:95→10:90)し、以下の物性値を有する標題化合物(45.06g)を得た。
1H-NMR (CDCl3): δ 8.14 (t, 1H), 7.03 (dd, 1H), 1.47 (s, 18H)。
実施例2(2)で製造した化合物(9.1g)、シアン化亜鉛(II)(7.32g)、テトラキス(トリフェニルホスフィン)パラジウム(0)(1.2g)の1−メチル−2−ピロリジノン(60mL)溶液を減圧下脱気した。マイクロウェーブ照射下、130℃で1時間撹拌した後、放冷した。反応溶液を酢酸エチル(100mL)で希釈した後、セライトろ過により不溶物を除去し、不溶物を酢酸エチル(50mL)で洗浄した。ろ液を分液し、水層を酢酸エチル(100mL)で再抽出した。有機層を合わせ、乾燥後、濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィーにより精製(酢酸エチル:ヘキサン=5:95→80:20)することで以下の物性値を有する標題化合物(2.1g)を得た。
TLC:Rf 0.25(酢酸エチル:ヘキサン=10:90)。
実施例2(3)で製造した化合物(1.56g)とヒドロキシルアミン塩酸塩(0.91g)のエタノール(40mL)溶液にN,N−ジイソプロピルエチルアミン(2.84mL)を加え、40℃で終夜撹拌した。反応溶液を濃縮し、得られた残渣を酢酸エチル(50mL)に溶解した。市水(50mL)を加え、洗浄した後、有機層を乾燥後、濃縮し、以下の物性値を有する未精製の標題化合物(1.93g)を得た。
LC/MS tR 0.60分; MS (ES+) m/z 271 (M+H) (条件a)。
実施例2(4)で製造した化合物(1.93g)の酢酸(10mL)溶液に無水酢酸(0.75mL)を加え、室温で1時間撹拌した。反応液に水酸化パラジウム(II)(20%、250mg)を加え、水素雰囲気下、室温で3時間撹拌した。反応液をセライトろ過し、ろ液を減圧濃縮し、以下の物性値を有する未精製の標題化合物(2.99g)を得た。
LC/MS tR 0.59分; MS (ES+) m/z 255 (M+H) (条件a)。
実施例2(5)で製造した化合物(2.6g)のメタノール(10mL)溶液に10%塩化水素/メタノール(6.5mL)溶液を加え、室温で10分間撹拌した。反応液にトルエンを加え濃縮し、以下の物性値を有する未精製の標題化合物(2.63g)を得た。
LC/MS tR 0.58分; MS (ES+) m/z 255 (M+H) (条件a)。
(3S)−7−[5−クロロ−2−(1H−1,2,3,4−テトラゾール−1−イル)フェニル]−5−オキソ−1,2,3,5−テトラヒドロインドリジン−3−カルボン酸(特許文献6の実施例9に記載)(3.0g)のジクロロメタン(15mL)溶液に、1−クロロ−N,N,2−トリメチル−1−プロペン−1−アミン(1.33mL)を氷冷下加え、0℃にて40分間撹拌した。トリメチルシリルジアゾメタン(2Mヘキサン溶液、8.4mL)を加えた後、さらに0℃で1時間撹拌した。濃塩酸(0.87mL)を氷冷下加え、室温で20分撹拌した。反応液に市水(50mL)を加え、ジクロロメタン(50mL)で2回抽出した。有機層を乾燥後、濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィーにより精製(酢酸エチル:ヘキサン=40:60→100:0)し、以下の物性値を有する標題化合物(2.32g)を得た。
LC/MS tR 0.80分; MS (ES+) m/z 390 (M+H) (条件a)。
実施例2(6)で製造した化合物(1.5g)および実施例2(7)で製造した化合物(1.0g)のアセトニトリル(50mL)溶液に炭酸カリウム(0.70g)を加え、80℃で17時間撹拌した。反応溶液を酢酸エチル(100mL)で希釈した後、市水(100mL)、飽和食塩水(200mL)で洗浄し、乾燥後、濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィーにより精製(酢酸エチル:ヘキサン=50:50→100:0、続いてメタノール:酢酸エチル=5:95)し、以下の物性値を有する標題化合物(1.11g)を得た。
LC/MS tR 0.81分; MS (ES+) m/z 590 (M+H) (条件a)。
実施例2(8)で製造した化合物(264mg)および炭酸ナトリウム(118mg)のアセトニトリル(10mL)/テトラヒドロフラン(5mL)懸濁液に、1−クロロメチル−4−フルオロ−1,4−ジアゾニアビシクロ[2.2.2]オクタン ビス(テトラフルオロボラート)(selectfluor(登録商標))(95mg)を加え氷/食塩浴にて冷却下で3時間撹拌した。反応溶液を酢酸エチル(20mL)で希釈し、亜硫酸ナトリウム水溶液(40mL)を加えた。水層を酢酸エチル(50mL)で2回抽出し、合わせた有機層を乾燥後、濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィーにより精製(アミノシリカ、酢酸エチル:ヘキサン=50:50→100:0、続いてメタノール:酢酸エチル=5:95)し、実施例2(9)のS体化合物とR体化合物の混合物(71.2mg)を得た。得られた混合物(20mg)を光学分割(DAICEL、CHIRALFLASH(登録商標)IC カラム、(粒子径:20μm;カラム長:100 x 30 mm I.D.)流速:24mL/min;カラム温度:室温;移動相(A):アセトニトリル;移動相(B):メタノール;イソクラティック(移動相(A):移動相(B)=90:10)20分;検出器:UV Yamazen UV-254W UV-Detector)によって精製し、標題化合物(実施例2(9)のS体化合物:7.9mg、実施例2(9)のR体化合物:7.7mg)を得た。なお、上記条件により光学分割した際における標題化合物の保持時間は、それぞれ13分(実施例2(9)のS体化合物)および9.5分(実施例2(9)のR体化合物)であった。
それぞれの標題化合物を下記括弧内の液体クロマトグラフィー条件により分析した際における物性値を以下に示す。
実施例2(9)のS体化合物:
LC tR 10.4分(カラムDAICEL CHIRALPAK(登録商標) IC 5μm 4.6mm×250mm、移動相アセトニトリル/メタノール=90/10、流速1.0mL/min)。
実施例2(9)のR体化合物:
LC tR 7.95分(カラムDAICEL CHIRALPAK(登録商標) IC 5μm 4.6mm×250mm、移動相アセトニトリル/メタノール=90/10、流速1.0mL/min)。
TLC:Rf 0.60(メタノール:酢酸エチル=5:95);
1H-NMR (CD3OD): δ 9.31 (s, 1H), 7.91 (dd, 1H), 7.74 - 7.65 (m, 3H), 6.44 (dd, 1H), 6.21 (s, 1H), 6.03 (s, 1H), 5.83 (dd, 1H), 3.39-3.06 (m, 2H), 2.62 - 2.48 (m, 2H);
LC tR 22.5分(カラムDAICEL CHIRALPAK(登録商標) IC 5μm 4.6mm×250mm、移動相ヘキサン/酢酸エチル=30/70、流速1.0mL/min);
[α]25 D=+44.1°(CH3OH、c=1.00)。
LC/MS tR 0.83分;MS(ES+) m/z 508(M+H) (条件a);
1H-NMR (d6-DMSO): δ 11.7 (brs, 1H), 9.64 (s, 1H), 7.87 (dd, 1H), 7.79 (brs, 2H), 7.75 (brs, 1H), 6.38 (dd, 1H), 6.00 (s, 1H), 5.92 (s, 1H), 5.69 (d, 1H), 3.23 - 2.96 (m, 2H), 2.58-2.22 (m, 2H)。
1H-NMR (CD3OD): δ 9.31 (s, 1H), 7.91 (dd, 1H), 7.74 - 7.65 (m, 3H), 6.44 (dd, 1H), 6.21 (s, 1H), 6.03 (s, 1H), 5.83 (dd, 1H), 3.39 - 3.06 (m, 2H), 2.62 - 2.48 (m, 2H);
LC tR 13.6分(カラムDAICEL CHIRALPAK(登録商標) IC 5μm 4.6mm×250mm、移動相ヘキサン/酢酸エチル=30/70、流速1.0mL/min);
[α]23 D= -39.6°(CH3OH、c=1.00)。
1H-NMR (CD3OD): δ 9.31 (s, 1H), 7.91 (dd, 1H), 7.74 - 7.65 (m, 3H), 6.44 (dd, 1H), 6.21 (s, 1H), 6.03 (s, 1H), 5.83 (dd, 1H), 3.39 - 3.06 (m, 2H), 2.62 - 2.48 (m, 2H);
LC/MS tR 0.82分;MS(ES+) m/z 508(M+H) (条件a)。
実施例2(8)で製造した化合物(1.47g)のTHF(28mL)溶液を0℃に冷却し、1,3−ジクロロ−5,5−ジメチルヒダントイン(491mg)を加え、30分間撹拌した。反応混合物に亜硫酸ナトリウム水溶液を加えて試薬を分解し、水を加え、酢酸エチルで抽出した。得られた有機層を水、1M水酸化ナトリウム水溶液、飽和食塩水で洗浄し、無水硫酸ナトリウムにて乾燥後、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィーにより精製(酢酸エチル:ヘキサン=70:30→100:0)し、標題化合物(1.10g)を得た。
実施例2(1)で製造した化合物の代わりに6−アミノニコチノニトリルを用いて、実施例2(2)→実施例2(4)→実施例2(5)→実施例2(6)と同様の操作を行うことにより、標題化合物を得た。
(6S)−2−[5−クロロ−2−(1H−1,2,3,4−テトラゾール−1−イル)フェニル]−4−オキソ−4H,6H,7H,8H−ピロロ[1,2−a]ピリミジン−6−カルボン酸(特許文献6の実施例336に記載)を用いて、実施例2(7)と同様の操作を行うことで、以下の物性値を有する標題化合物を得た。
LC/MS tR 0.75分;MS(ES+) m/z 391(M+H) (条件a)。
実施例2(6)で製造した化合物と実施例3(1)の化合物を用いて、実施例2(8)と同様の操作を行うことで、以下の物性値を有する標題化合物を得た。
LC/MS tR 0.79分; MS (ES+) m/z 591 (M+H) (条件a)。
実施例3(2)で製造した化合物を用いて、実施例2(9)と同様の操作を行うことで、以下の物性値を有する標題化合物を得た。なお、光学分割(DAICEL、CHIRALFLASH(登録商標)IC カラム、(粒子径:20μm;カラム長:100 x 30 mm I.D.)流速:24mL/min;カラム温度:室温;移動相:アセトニトリル;検出器:UV Yamazen UV-254W UV-Detector)した際における標題化合物の保持時間は、それぞれ13.7分(実施例3(3)のS体化合物)および8.1分(実施例3(3)のR体化合物)であった。
実施例3(3)のS体化合物:
LC tR 4.15分(カラムDAICEL CHIRALPAK(登録商標) IC 3μm 4.6mm×250mm、移動相メタノール、流速1.0mL/min)。
実施例3(3)のR体化合物:
LC tR 3.75分(カラムDAICEL CHIRALPAK(登録商標) IC 3μm 4.6mm×250mm、移動相メタノール、流速1.0mL/min)。
TLC:Rf 0.65(メタノール:酢酸エチル=5:95);
1H-NMR (CD3OD): δ 9.40 (s, 1H), 7.95 - 7.86 (m,2H), 7.76 (dd, 1H), 7.68 (d, 1H), 6.44 (dd, 1H), 6.41 (s, 1H), 5.78 (dd, 1H), 3.12 (m, 1H), 2.90 (m, 1H), 2.62 (m, 1H) 2.41 (m, 1H);
LC tR 4.23分(カラムDAICEL CHIRALPAK(登録商標) IC 3μm 4.6mm×250mm、移動相メタノール、流速1.0mL/min);
[α]25 D=+74.6°(CH3OH、c=1.00)。
1H-NMR (CD3OD): δ 9.44 (s, 1H), 7.95 - 7.85 (m,2H), 7.78 (dd, 1H), 7.71 (d, 1H), 6.50 (dd, 1H), 6.42 (s, 1H), 5.80 (dd, 1H), 3.13 (m, 1H), 2.98 (m, 1H), 2.72 (m, 1H) 2.43 (m, 1H);
LC tR 4.63分(カラムDAICEL CHIRALPAK(登録商標) IC 3μm 4.6mm×250mm、移動相メタノール、流速1.0mL/min)。
エチル (3S)−7−(2−アミノ−5−クロロフェニル)−5−オキソ−1,2,3,5−テトラヒドロインドリジン−3−カルボキシレート(特許文献6の実施例7に記載)(2.0g)のアセトニトリル溶液(15mL)に、冷却(0℃)下、トリメチルシリルアジド(1.39g)および亜硝酸アミル(1.41g)を加えた。混合物を室温にて1時間撹拌した後、濃縮した。残渣をカラムクロマトグラフィー(酢酸エチル:ヘキサン=10:90→100:0)にて精製し、以下の物性値を有する標題化合物(1.89g)を得た。
TLC:Rf 0.75 (メタノール:酢酸エチル=5:95)。
実施例4(1)で製造した化合物(15.0g)のN,N−ジメチルホルムアミド溶液(45mL)に、プロピオルアミド(3.18g)、(R)−3,4−ジヒドロキシ−5−((S)−1,2−ジヒドロキシエチル)フラン−2(5H)−オン(1.47g)および硫酸銅(II)(0.33g)を加えた。混合物を50℃にて10分撹拌した後、水を加えた。析出物を濾取し、水で洗浄後、乾燥し、以下の物性値を有する標題化合物(17.5g)を得た。
LC/MS tR 0.69 分: MS (ES+) m/z 428 (M+H) (条件b)。
実施例4(2)で製造した化合物(100mg)の1,4−ジオキサン溶液(10mL)に、5M塩酸(5 mL)を加えた。混合物を60℃にて5時間撹拌した後、室温にて5M 水酸化ナトリウム水溶液(5mL)を加え、酢酸エチルで抽出した。有機層を乾燥後濃縮し、以下の物性値を有する標題化合物(61.7mg)を得た。
LC/MS tR 0.60 分: MS (ES+) m/z 400 (M+H) (条件b)。
実施例4(3)で製造した化合物(6.10g)のN,N−ジメチルホルムアミド溶液(61mL)に、tert−ブチル N−[4−(2−ブロモアセチル)フェニル]カルバマート(7.19g)およびN,N−ジイソプロピルエチルアミン(5.3mL)を加えた。混合物を室温にて3日間撹拌した後、水と酢酸エチルを加えた。析出物を濾過にて集めて水で洗浄後、乾燥し、以下の物性値を有する標題化合物(3.93g)を得た。
LC/MS tR 0.90分: MS (ES+) m/z 633 (M+H) (条件b)。
実施例4(4)で製造した化合物(3.93g)をトルエン(79mL)と氷酢酸(3.9mL)に溶解し、酢酸アンモニウム(9.57g)を加えた。混合物を加熱還流下、4時間撹拌した後、水と酢酸エチルを加えた。有機層を水で洗浄後、乾燥し、以下の物性値を有する標題化合物(3.98g)を得た。
LC/MS tR 0.73分: MS (ES+) m/z 613 (M+H) (条件b)。
実施例4(5)で製造した化合物(3.81g)のピリジン溶液(76mL)に、冷却(0℃)下、無水トリフルオロ酢酸(4.3mL)を加えた。混合物を0℃にて2時間撹拌した後、水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、乾燥して濃縮し、得られた残渣をテトラヒドロフランに溶解し、アンモニア水を加え、30分撹拌した。混合物を濃縮し、残渣をカラムクロマトグラフィー(ジオールシリカゲル、酢酸エチル:ヘキサン=50:50→80:20)(アミノシリカゲル、酢酸エチル:ヘキサン=50:50→80:20)にて精製し、以下の物性値を有する標題化合物(2.39g)を得た。
LC/MS tR 0.83 分: MS (ES+) m/z 595 (M+H) (条件b)。
実施例4(6)で製造した化合物(2.00g)のN,N−ジメチルホルムアミド溶液(20mL)に、冷却(0℃)下、N,N−ジイソプロピルエチルアミン(0.87mL)および2−(トリメチルシリル)エトキシメチルクロリド(0.66mL)を加えた。混合物を室温にて8時間撹拌した後、飽和塩化アンモニウム水溶液を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、乾燥し濃縮した。残渣をカラムクロマトグラフィー(ジオールシリカゲル、酢酸エチル:ヘキサン=30:70→50:50)にて精製し、以下の物性値を有する標題化合物(2.27g)を得た。
LC/MS tR 1.17分: MS (ES+) m/z 725 (M+H) (条件b)。
実施例4(7)で製造した化合物(560mg)をテトラヒドロフラン(5.6mL)とアセトニトリル(2.8mL)に溶解し、−10℃にて炭酸ナトリウム(205mg)および1−クロロメチル−4−フルオロ−1,4−ジアゾニアビシクロ[2.2.2]オクタン ビス(テトラフルオロボラート)(219mg)を加え、6時間撹拌した。反応混合物を酢酸エチルで希釈し、水を加え分液し、水層を酢酸エチルで抽出した。有機層を合わせ、飽和食塩水で洗浄し、乾燥後濃縮した。残渣をカラムクロマトグラフィー(酢酸エチル:ヘキサン=30:70→50:50)にて精製し、以下の物性値を有する標題化合物(277mg)を得た。
LC/MS tR 1.30 分: MS (ES+) m/z 743 (M+H) (条件a)。
実施例4(8)で製造した化合物(427mg)の1,4−ジオキサン溶液(4.3mL)に、5M塩酸水溶液(0.43mL)を加えた。混合物を室温にて30分撹拌した後、飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、乾燥し濃縮した。残渣をカラムクロマトグラフィー(ジオールシリカゲル、酢酸エチル:ヘキサン=35:65→50:50)にて精製し、以下の物性値を有する標題化合物(320mg)を得た。
LC/MS tR 1.11 分: MS (ES+) m/z 613 (M+H) (条件a)。
LC/MS tR 0.79 分: MS (ES+) m/z 513 (M+H) (条件a);
1H NMR (300 MHz, methanol-d4); δ 8.88 (s, 1H), 7.73-7.65 (m, 3H), 7.30 (d, 2H), 6.75 (d, 2H), 6.11 (s, 1H), 6.08 (s, 1H), 5.70 (d, 1H), 3.42 (m, 1H), 3.10 (m, 1H), 2.61 (m, 1H), 2.39 (m, 1H)。
(3S)−3−[5−(6−アミノ−2−フルオロ−3−ピリジニル)−1H−イミダゾール−2−イル]−7−[5−クロロ−2−(1H−テトラゾール−1−イル)フェニル]−2,3−ジヒドロ−5(1H)−インドリジノン(比較例1(1)とする。):
(1)in vitroアッセイ
本発明化合物のヒト血液凝固第XIa因子、第VIIa因子、第IXa因子、第Xa因子、第XIIa因子、血漿カリクレインおよびトロンビン阻害活性を評価した。各酵素液に発色基質液を添加し、405nmの吸光度を37℃で15秒間隔に連続的に5分間測定し、基質分解速度(mOD/min)を求めた。本発明化合物の各酵素に対する50%阻害濃度(IC50)は、本発明化合物の濃度の自然対数変換値と下記方程式に従って求めた酵素阻害率から、最小二乗法による直線回帰を行い、算出した。
本発明化合物の酵素阻害率(%)は、以下の式を用いて算出した。:
ヒト血液凝固第XIa因子(Haematologic Technologies Inc.)阻害活性は、300 mM NaCl、10 mM KCl、2 mg/mL PEG6000、100 mM HEPES−NaOH(pH7.4)を含む緩衝液で0.1 U/mLに調整した酵素液および蒸留水で1 mMに調整したS−2366(pyroglu−Pro−Arg−pNA、CHROMOGENIX)を用いて測定した。
ヒト血漿カリクレイン(Enzyme Research Laboratories Ltd.)阻害活性は、400 mM NaCl、10 mg/mL PEG6000および200 mMリン酸緩衝液(pH7.4)を含む緩衝液で20 mU/mLに調整した酵素液および蒸留水で500 μMに調整したS−2302(H−D−Pro−Phe−Arg−pNA、CHROMOGENIX)を用いて測定した。
ヒト血液凝固第Xa因子(Sekisui Diagnostics LLC.)阻害活性およびヒトトロンビン(Sigma)阻害活性は、300 mM NaCl、4 mg/mL PEG6000、100 mM トリス−HCl(pH7.4)を含む緩衝液でそれぞれ0.5 U/mLまたは0.25 U/mLに調整した各酵素液および蒸留水でそれぞれ1 mMに調整したS−2222[Bz−Ile−Glu(γ−OR)−Gly−Arg−pNA・HCl,R=H(50%) and R=CH3(50%)、CHROMOGENIX]またはS−2366を用いて測定した。
ヒト血液凝固第XIIa因子(Enzyme Research Laboratories Ltd.)阻害活性は、300 mM NaCl、100 mM トリス−HCl(pH7.4)を含む緩衝液で0.78 U/mLに調整した酵素液および蒸留水で1mMに調整したS−2302を用いて測定した。
ヒト血液凝固第IXa因子(Sekisui Diagnostics LLC.)阻害活性は、200 mM NaCl、10 mM CaCl2、60%エチレングリコール、100 mM トリス-HCl(pH7.4)を含む緩衝液で30 U/mLに調整した酵素液および蒸留水で10 mMに調整したSpectrozume FIXa(H−D−Leu−Ph’Gly−Arg−pNA・2AcOH、Sekisui Diagnostics LLC.)を用いて測定した。
ヒト血液凝固第VIIa因子(Sekisui Diagnostics LLC.)阻害活性は、300 mM NaCl、10 mM CaCl2、10 mg/mL PEG6000、100 mM HEPES−NaOH(pH7.4)、組換えヒト組織因子(アリレザ R.リザイエらの方法(プロテイン エクスプレッション アンド ピューリフィケーション(Protein expression and purification)、1992年、第3巻、第6号、453〜460頁)に従って製造した)を含む緩衝液で200U/mLに調整した酵素液および蒸留水で10mMに調整したS−2288(H−D−Ile−Pro−Arg−pNA、CHROMOGENIX)を用いて測定した。
全自動血液凝固測定装置(CA−1500、Sysmex Corporation)を用いて、活性化部分トロンボプラスチン時間(APTT)およびプロトロンビン時間(PT)を測定した。APTTまたはPT測定に対して、血液凝固試験用標準ヒト血漿(Siemens Healthcare Diagnostics GmbH)を本発明化合物希釈液と混合し、その後、血塊形成を開始させるために、APTT試薬(Siemens Healthcare Diagnostics GmbH)および0.02M塩化カルシウムまたはPT試薬(Siemens Healthcare Diagnostics GmbH)の自動添加を行った。本発明化合物の抗凝固活性(APTT×2またはPT×2)は、ビヒクル(1%DMSO)群における凝固時間を倍にするために必要な濃度として表した。APTT×2またはPT×2は、凝固時間の倍単位での増加に対して本発明の化合物の濃度をプロットすることによって決定した。
本発明化合物を単回0.1mg/kg、i.v.用量(媒体:20%HP−β−CD溶液)として静脈内注射投与、及び1mg/kg、p.o.用量(媒体:0.5%メチルセルロース溶液)として強制経口投与により絶食オスCrj:CD(SD)ラットに与えた。静脈内注射投与後、0.08、0.25、0.5、1、3、7時間で、または経口投与後、0.08、0.25、0.5、1、2、4、6、8、24時間で、ヘパリン処理シリンジに、頸静脈から血液試料を採取した。遠心によって血漿を得て、血漿濃度の測定まで−20℃で保管した。
(1)CYP阻害活性
競合阻害活性
ミダゾラム及び本発明化合物をヒト由来肝ミクロソーム懸濁液に添加し37℃で3分間振盪させた後、試料中の1’−ヒドロキシミダゾラム濃度をLC/MS/MSによって分析した。
本発明化合物をヒト由来肝ミクロソーム懸濁液に添加し37℃で30分間振盪させた後ミダゾラムを添加し、更に3分間振盪させ、振盪後の試料中の1’−ヒドロキシミダゾラム濃度をLC/MS/MSによって分析した。
本発明化合物をヒト血清で懸濁したヒト由来肝細胞懸濁液に添加し37℃で10分間振盪させた後、ミダゾラムを添加し更に90分間振盪させ、振盪後の試料中の1’−ヒドロキシミダゾラム濃度をLC/MS/MSによって分析した。分析用カラム(Shim−pack XR−ODSII、2.0mm×75mm、2.2μm)および移動相(水中0.1%ギ酸およびアセトニトリル中0.1%ギ酸、流速0.5mL/分)を使用した。陽イオン検出により、多重反応モニタリング(MRM)モードでこの系を使用した。本発明化合物の試料中濃度は10μmol/L、30μmol/L、100μmol/Lとした。
(1)hERG阻害作用
本発明化合物のhERG阻害活性を、以下の手順により測定した。
hERGの遺伝子導入CHO−K1細胞を使用し、刺激パルスにより誘導されるhERGチャンネル電流(IKr)を、アンフォテリシン穿孔パッチクランプ法によって全自動パッチクランプシステムを用いて測定した。刺激パルスは保持電圧:−80mV、脱分極電圧:+40mV(2秒間)、再分極電圧:−50mV(2秒間)とし、再分極電圧後に誘導される最大tail電流を測定した。刺激パルスは本発明化合物の添加前および添加5分後の2回適用し、添加前に対する最大tail電流の変化率を求めた。本発明化合物はジメチルスルホキシド(DMSO)溶液とし、1%の濃度で細胞外液に添加した。hERGチャンネルの阻害率(%)は本発明化合物の添加前後の最大tail電流の変化率を媒体処置群での変化率で補正することにより求めた。
本発明化合物のステアトーシス誘導作用を、以下の手順により測定した。
ヒト不死化肝細胞株Fa2N−4に培地に6.25、12.5、25、50、100μMの濃度の本発明化合物DMSO溶液を1%添加し、72時間暴露させた後、Nile Redを添加し、励起波長485nm、蛍光波長570nmで細胞の蛍光強度を測定した。蛍光測定値が媒体処置の160%以上の値を示した場合、ステアトーシス誘導作用ありと判定した。
製剤例1
以下の各成分を常法により混合した後打錠して、一錠中に10mgの活性成分を含有する錠剤1万錠を得る。
・(3S)−3−[5−(6−アミノ−2−フルオロ−3−ピリジニル)−4−フルオロ−1H−イミダゾール−2−イル]−7−[5−クロロ−2−(1H−テトラゾール−1−イル)フェニル]−2,3−ジヒドロ−5(1H)−インドリジノン…100g
・カルボキシメチルセルロースカルシウム … 20g
・ステアリン酸マグネシウム … 10g
・微結晶セルロース … 870g
以下の各成分を常法により混合した後、除塵フィルターでろ過し、5mlずつアンプルに充填し、オートクレーブで加熱滅菌して、1アンプル中20mgの活性成分を含有するアンプル1万本を得る。
・(3S)−3−[5−(6−アミノ−2−フルオロ−3−ピリジニル)−4−フルオロ−1H−イミダゾール−2−イル]−7−[5−クロロ−2−(1H−テトラゾール−1−イル)フェニル]−2,3−ジヒドロ−5(1H)−インドリジノン…200g
・マンニトール … 20g
・蒸留水 … 50L
Claims (6)
- 一般式(I)で示される化合物が、(3S)−3−[5−(6−アミノ−2−フルオロ−3−ピリジニル)−4−フルオロ−1H−イミダゾール−2−イル]−7−[5−クロロ−2−(1H−テトラゾール−1−イル)フェニル]−2,3−ジヒドロ−5(1H)−インドリジノンである請求項1記載の化合物、その塩、その溶媒和物、またはそのN−オキシド体。
- 一般式(I)で示される化合物が、(6S)−6−[2−(6−アミノ−2−フルオロ−3−ピリジニル)−4−フルオロ−1H−イミダゾール−5−イル]−2−[5−クロロ−2−(1H−テトラゾール−1−イル)フェニル]−7,8−ジヒドロピロロ[1,2−a]ピリミジン−4(6H)−オンである請求項1記載の化合物、その塩、その溶媒和物、またはそのN−オキシド体。
- 一般式(I)で示される化合物が、1−(2−{(3S)−3−[5−(4−アミノフェニル)−4−フルオロ−1H−イミダゾール−2−イル]−5−オキソ−1,2,3,5−テトラヒドロ−7−インドリジニル}−4−クロロフェニル)−1H−1,2,3−トリアゾール−4−カルボニトリルである請求項1記載の化合物、その塩、その溶媒和物、またはそのN−オキシド体。
- 請求項1〜4のいずれか1項記載の化合物、その塩、その溶媒和物、またはそのN−オキシド体を活性成分とする医薬組成物。
- 前記活性成分がFXIa阻害活性を有する、請求項5に記載の医薬組成物。
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JP2017218449A (ja) * | 2016-06-06 | 2017-12-14 | 小野薬品工業株式会社 | ジヒドロインドリジノン誘導体を含有する医薬組成物 |
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CN106132962B (zh) | 2014-01-31 | 2018-09-07 | 百时美施贵宝公司 | 作为凝血因子xia抑制剂的具有芳族p2’基团的大环化合物 |
NO2760821T3 (ja) | 2014-01-31 | 2018-03-10 | ||
ES2714283T3 (es) | 2014-09-04 | 2019-05-28 | Bristol Myers Squibb Co | Macrociclos de diamida que son inhibidores de FXIa |
US9453018B2 (en) | 2014-10-01 | 2016-09-27 | Bristol-Myers Squibb Company | Pyrimidinones as factor XIa inhibitors |
SG11202105697SA (en) * | 2018-11-30 | 2021-06-29 | Ono Pharmaceutical Co | Novel crystal of (3s)-3-[2-(6-amino-2-fluoropyridine-3-yl)-4-fluoro-1h-imidazole-5-yl]-7-[5-chloro-2-(1h-tetrazole-1-yl)phenyl]-2,3-dihydroindolizine-5(1h)-one |
KR102242187B1 (ko) * | 2019-06-04 | 2021-04-20 | 주식회사 우정바이오 | 실내 표면 및 공기 살균 정화 장치 |
US11518766B2 (en) | 2019-06-28 | 2022-12-06 | Shanghai Jemincare Pharmaceuticals Co., Ltd. | Tricyclic compound, preparation method therefor and use thereof |
WO2023002984A1 (ja) * | 2021-07-20 | 2023-01-26 | 小野薬品工業株式会社 | イミダゾール化合物の製造方法 |
TWI833610B (zh) * | 2022-03-21 | 2024-02-21 | 大陸商上海濟煜醫藥科技有限公司 | 三并環類化合物製備方法及其中間體 |
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JP2017218449A (ja) * | 2016-06-06 | 2017-12-14 | 小野薬品工業株式会社 | ジヒドロインドリジノン誘導体を含有する医薬組成物 |
JP6992284B2 (ja) | 2016-06-06 | 2022-01-13 | 小野薬品工業株式会社 | ジヒドロインドリジノン誘導体を含有する医薬組成物 |
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