JP2011513475A - ポリ(adp−リボース)ポリメラーゼ(parp)の阻害剤としての三環式誘導体 - Google Patents
ポリ(adp−リボース)ポリメラーゼ(parp)の阻害剤としての三環式誘導体 Download PDFInfo
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- JP2011513475A JP2011513475A JP2010550258A JP2010550258A JP2011513475A JP 2011513475 A JP2011513475 A JP 2011513475A JP 2010550258 A JP2010550258 A JP 2010550258A JP 2010550258 A JP2010550258 A JP 2010550258A JP 2011513475 A JP2011513475 A JP 2011513475A
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- XFCLJVABOIYOMF-QPLCGJKRSA-N toremifene Chemical compound C1=CC(OCCN(C)C)=CC=C1C(\C=1C=CC=CC=1)=C(\CCCl)C1=CC=CC=C1 XFCLJVABOIYOMF-QPLCGJKRSA-N 0.000 description 1
- 229960005026 toremifene Drugs 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
- 231100000765 toxin Toxicity 0.000 description 1
- 108700012359 toxins Proteins 0.000 description 1
- 206010044325 trachoma Diseases 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 230000037317 transdermal delivery Effects 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- 230000008733 trauma Effects 0.000 description 1
- 229960003181 treosulfan Drugs 0.000 description 1
- 229960001727 tretinoin Drugs 0.000 description 1
- 150000004654 triazenes Chemical class 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- ZNRGQMMCGHDTEI-ITGUQSILSA-N tropisetron Chemical compound C1=CC=C2C(C(=O)O[C@H]3C[C@H]4CC[C@@H](C3)N4C)=CNC2=C1 ZNRGQMMCGHDTEI-ITGUQSILSA-N 0.000 description 1
- 229960003688 tropisetron Drugs 0.000 description 1
- 229950010147 troxacitabine Drugs 0.000 description 1
- RXRGZNYSEHTMHC-BQBZGAKWSA-N troxacitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1O[C@@H](CO)OC1 RXRGZNYSEHTMHC-BQBZGAKWSA-N 0.000 description 1
- 201000008827 tuberculosis Diseases 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 102000003298 tumor necrosis factor receptor Human genes 0.000 description 1
- 150000004917 tyrosine kinase inhibitor derivatives Chemical class 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- VBEQCZHXXJYVRD-GACYYNSASA-N uroanthelone Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CS)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)C(C)C)[C@@H](C)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CCSC)NC(=O)[C@H](CS)NC(=O)[C@@H](NC(=O)CNC(=O)CNC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CS)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CS)NC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(N)=O)C(C)C)[C@@H](C)CC)C1=CC=C(O)C=C1 VBEQCZHXXJYVRD-GACYYNSASA-N 0.000 description 1
- 206010046766 uterine cancer Diseases 0.000 description 1
- LNPDTQAFDNKSHK-UHFFFAOYSA-N valdecoxib Chemical compound CC=1ON=C(C=2C=CC=CC=2)C=1C1=CC=C(S(N)(=O)=O)C=C1 LNPDTQAFDNKSHK-UHFFFAOYSA-N 0.000 description 1
- 229940005605 valeric acid Drugs 0.000 description 1
- MSRILKIQRXUYCT-UHFFFAOYSA-M valproate semisodium Chemical compound [Na+].CCCC(C(O)=O)CCC.CCCC(C([O-])=O)CCC MSRILKIQRXUYCT-UHFFFAOYSA-M 0.000 description 1
- 229960000604 valproic acid Drugs 0.000 description 1
- 229960000653 valrubicin Drugs 0.000 description 1
- ZOCKGBMQLCSHFP-KQRAQHLDSA-N valrubicin Chemical compound O([C@H]1C[C@](CC2=C(O)C=3C(=O)C4=CC=CC(OC)=C4C(=O)C=3C(O)=C21)(O)C(=O)COC(=O)CCCC)[C@H]1C[C@H](NC(=O)C(F)(F)F)[C@H](O)[C@H](C)O1 ZOCKGBMQLCSHFP-KQRAQHLDSA-N 0.000 description 1
- 208000027185 varicose disease Diseases 0.000 description 1
- 239000013598 vector Substances 0.000 description 1
- 230000002861 ventricular Effects 0.000 description 1
- 229960001722 verapamil Drugs 0.000 description 1
- 229960003048 vinblastine Drugs 0.000 description 1
- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 description 1
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 1
- 229960004528 vincristine Drugs 0.000 description 1
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 1
- 229960005212 vindesine sulfate Drugs 0.000 description 1
- NMDYYWFGPIMTKO-HBVLKOHWSA-N vinflunine Chemical compound C([C@@](C1=C(C2=CC=CC=C2N1)C1)(C2=C(OC)C=C3N(C)[C@@H]4[C@@]5(C3=C2)CCN2CC=C[C@]([C@@H]52)([C@H]([C@]4(O)C(=O)OC)OC(C)=O)CC)C(=O)OC)[C@H]2C[C@@H](C(C)(F)F)CN1C2 NMDYYWFGPIMTKO-HBVLKOHWSA-N 0.000 description 1
- 229960000922 vinflunine Drugs 0.000 description 1
- GBABOYUKABKIAF-GHYRFKGUSA-N vinorelbine Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-GHYRFKGUSA-N 0.000 description 1
- 229960002066 vinorelbine Drugs 0.000 description 1
- 201000002498 viral encephalitis Diseases 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
- 229940072168 zocor Drugs 0.000 description 1
- 229960004276 zoledronic acid Drugs 0.000 description 1
- 229960000641 zorubicin Drugs 0.000 description 1
- FBTUMDXHSRTGRV-ALTNURHMSA-N zorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(\C)=N\NC(=O)C=1C=CC=CC=1)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 FBTUMDXHSRTGRV-ALTNURHMSA-N 0.000 description 1
- VLCYCQAOQCDTCN-ZCFIWIBFSA-N α-difluoromethylornithine Chemical compound NCCC[C@@](N)(C(F)F)C(O)=O VLCYCQAOQCDTCN-ZCFIWIBFSA-N 0.000 description 1
- 239000002076 α-tocopherol Substances 0.000 description 1
- 235000004835 α-tocopherol Nutrition 0.000 description 1
Classifications
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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
- C07D471/06—Peri-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/16—Emollients or protectives, e.g. against radiation
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- 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
- C07D471/12—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 three hetero rings
- C07D471/16—Peri-condensed systems
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- Pharmacology & Pharmacy (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
Description
aは、0、1、2、又は3であり;
各bは、1又は2であり;
各cは、独立して、0、1、2、3、4、5、又は6であり;
各dは、独立して、0又は1であり;
各eは、独立して、0又は1であり;
各fは、独立して、0又は1であり;
各gは、独立して、0、1、2、3、4、5、又は6であり;
各hは、独立して、0又は1であり;
jは、0、1、2、又は3であり;
の化合物、又はその薬学的に許容される塩、立体異性体、若しくは互変異性体を提供する。
の化合物、又はその薬学的に許容される塩、立体異性体、若しくは互変異性体も提供する。
の化合物、又はその薬学的に許容される塩、立体異性体、若しくは互変異性体も提供する。
の化合物、又はその薬学的に許容される塩、立体異性体、若しくは互変異性体も提供する。
の化合物、又はその薬学的に許容される塩、立体異性体、若しくは互変異性体も提供する。
N−メチル[4−(6−オキソ−6,7,8,9−テトラヒドロ−2,7,9b−トリアザベンゾ[cd]アズレン−1−イル)フェニル]メタンアミニウムトリフルオロアセテート;
N−メチル[4−(5−オキソ−4,5−ジヒドロ−3H−1,4,8b−トリアザアセナフチレン−2−イル)フェニル]メタンアミニウムトリフルオロアセテート;
N−メチル[4−(6−オキソ−3,4,5,6−テトラヒドロ−2H−アゼピノ[5,4,3−cd]インダゾール−2−イル)フェニル]メタンアミニウムトリフルオロアセテート;
N,N−ジメチル[4−(6−オキソ−3,4,5,6−テトラヒドロ−2H−アゼピノ[5,4,3−cd]インダゾール−2−イル)フェニル]メタンアミニウムトリフルオロアセテート;
N2,N2−ジメチル−N−[4−(1−オキソ−1,2,3,4−テトラヒドロアゼピノ[3,4,5−hi]インドリジン−5−イル)フェニル]グリシンアミド;
3−[4−(8−フルオロ−6−オキソ−3,4,5,6−テトラヒドロ−2H−アゼピノ[5,4,3−cd]インダゾール−2−イル)フェニル]ピペリジニウムトリフルオロアセテート;
8−フルオロ−2−{4−[(3R)−ピペリジン−3−イル]フェニル}−2,3,4,5−テトラヒドロ−6H−アゼピノ[5,4,3−cd]インダゾール−6−オン;
8−フルオロ−2−{4−[(3S)−ピペリジン−3−イル]フェニル}−2,3,4,5−テトラヒドロ−6H−アゼピノ[5,4,3−cd]インダゾール−6−オン;
N,N−ジメチル[4−(6−オキソ−6,7,8,9−テトラヒドロ−2,7,9b−トリアザベンゾ[cd]アズレン−1−イル)フェニル]メタンアミニウムトリフルオロアセテート;
N−[4−(6−オキソ−6,7,8,9−テトラヒドロ−2,7,9b−トリアザベンゾ[cd]アズレン−1−イル)ベンジル]プロパン−2−アミニウムトリフルオロアセテート;
2−[4−(6−オキソ−6,7,8,9−テトラヒドロ−2,7,9b−トリアザベンゾ[cd]アズレン−1−イル)ベンジル]−2,7−ジアゾニアスピロ[4.5]デカンビス(トリフルオロアセテート);
1−メチル−4−({[4−(6−オキソ−6,7,8,9−テトラヒドロ−2,7,9b−トリアザベンゾ[cd]アズレン−1−イル)ベンジル]アンモニオ}メチル)ピペリジニウムビス(トリフルオロアセテート);
N,N−ジメチル[4−(5−オキソ−4,5−ジヒドロ−3H−1,4,8b−トリアザアセナフチレン−2−イル)フェニル]メタンアミニウムトリフルオロアセテート;
2−[4−(5−オキソ−4,5−ジヒドロ−3H−1,4,8b−トリアザアセナフチレン−2−イル)ベンジル]−2,7−ジアゾニアスピロ[4.5]デカンビス(トリフルオロアセテート);
1−メチル−4−({[4−(5−オキソ−4,5−ジヒドロ−3H−1,4,8b−トリアザアセナフチレン−2−イル)ベンジル]アンモニオ}メチル)ピペリジニウムビス(トリフルオロアセテート);
N−[4−(5−オキソ−4,5−ジヒドロ−3H−1,4,8b−トリアザアセナフチレン−2−イル)ベンジル]プロパン−2−アミニウムトリフルオロアセテート;
2−[4−(6−オキソ−3,4,5,6−テトラヒドロ−2H−アゼピノ[5,4,3−cd]インダゾール−2−イル)ベンジル]−2,7−ジアゾニアスピロ[4.5]デカンビス(トリフルオロアセテート);
[4−(8−フルオロ−6−オキソ−3,4,5,6−テトラヒドロ−2H−アゼピノ[5,4,3−cd]インダゾール−2−イル)フェニル]−N,N−ジメチルメタンアミニウムトリフルオロアセテート;
5−フェニル−3,4−ジヒドロアゼピノ[3,4,5−hi]インドリジン−1(2H)−オン;
エチル4−(1−オキソ−1,2,3,4−テトラヒドロアゼピノ[3,4,5−hi]インドリジン−5−イル)ベンゾアート;
5−(4−ニトロフェニル)−3,4−ジヒドロアゼピノ[3,4,5−hi]インドリジン−1(2H)−オン;
5−[4−(ヒドロキシメチル)フェニル]−3,4−ジヒドロアゼピノ[3,4,5−hi]インドリジン−1(2H)−オン;
N−[4−(1−オキソ−1,2,3,4−テトラヒドロアゼピノ[3,4,5−hi]インドリジン−5−イル)フェニル]ニコチンアミド;
N−[4−(1−オキソ−1,2,3,4−テトラヒドロアゼピノ[3,4,5−hi]インドリジン−5−イル)フェニル]ピリジン−2−カルボキサミド;
N−[4−(1−オキソ−1,2,3,4−テトラヒドロアゼピノ[3,4,5−hi]インドリジン−5−イル)フェニル]−2−ピロリジン−1−イルアセトアミド;
1−メチル−N−[4−(1−オキソ−1,2,3,4−テトラヒドロアゼピノ[3,4,5−hi]インドリジン−5−イル)フェニル]ピペリジン−4−カルボキサミド;
3−({[4−(1−オキソ−1,2,3,4−テトラヒドロアゼピノ[3,4,5−hi]インドリジン−5−イル)フェニル]アミノ}カルボニル)アゼチジニウムクロリド;
(3S)−1−メチル−N−[4−(1−オキソ−1,2,3,4−テトラヒドロアゼピノ[3,4,5−hi]インドリジン−5−イル)フェニル]ピペリジン−3−カルボキサミド;
(3R)−1−メチル−N−[4−(1−オキソ−1,2,3,4−テトラヒドロアゼピノ[3,4,5−hi]インドリジン−5−イル)フェニル]ピペリジン−3−カルボキサミド;
(2S)−1−メチル−N−[4−(1−オキソ−1,2,3,4−テトラヒドロアゼピノ[3,4,5−hi]インドリジン−5−イル)フェニル]ピペリジン−2−カルボキサミド;
(2R)−1−メチル−N−[4−(1−オキソ−1,2,3,4−テトラヒドロアゼピノ[3,4,5−hi]インドリジン−5−イル)フェニル]ピペリジン−2−カルボキサミド;
5−{4−[(ジメチルアミノ)メチル]フェニル}−3,4−ジヒドロアゼピノ[3,4,5−hi]インドリジン−1(2H)−オン;
5−{4−[(メチルアミノ)メチル]フェニル}−3,4−ジヒドロアゼピノ[3,4,5−hi]インドリジン−1(2H)−オン;
5−{4−[(4−メチルピペラジン−1−イル)メチル]フェニル}−3,4−ジヒドロアゼピノ[3,4,5−hi]インドリジン−1(2H)−オン;
5−{4−[(イソプロピルアミノ)メチル]フェニル}−3,4−ジヒドロアゼピノ[3,4,5−hi]インドリジン−1(2H)−オン;
5−(4−{[(2−ヒドロキシエチル)アミノ]メチル}フェニル)−3,4−ジヒドロアゼピノ[3,4,5−hi]インドリジン−1(2H)−オン;
及び、その薬学的に許容される塩、遊離塩基、及び互変異性体である。
チロシンキナーゼ阻害剤、上皮由来の成長因子の阻害剤、線維芽細胞由来の成長因子の阻害剤、血小板由来の成長因子の阻害剤、MMP(マトリックスメタロプロテアーゼ)阻害剤、インテグリン阻害剤、インターフェロン−α、インターロイキン−12、ペントサン多硫酸塩、シクロオキシゲナーゼ阻害剤、カルボキシアミドトリアゾール、コンブレタスタチンA−4、スクアラミン、6−O−クロロアセチル−カルボニル)−フマギロール、サリドマイド、アンギオスタチン、トロポニン−1、又はVEGFに対する抗体から選択される。1つの実施態様においては、エストロゲン受容体モジュレータは、タモキシフェン又はラロキシフェンである。
AcOH:酢酸;DCE:ジクロロエタン;DCM:ジクロロメタン;DMF:ジメチルホルムアミド;DMSO:ジメチルスルホキシド;EtOH:エタノール;EtOAc:酢酸エチル;i−PrOH:2−プロパノール;MeCN:アセトニトリル;MeOH:メタノール;THF:テトラヒドロフラン;Et2O:ジエチルエーテル;TFA:トリフルオロ酢酸;TIPS:トリイソプロピルシラン;DIBAL−H:ジイソブチルアルミニウムヒドリド;NaHMDS:ナトリウムビス(トリメチルシリル)アミド;dppf:1,1’−ビス[ジフェニルホスフィン]フェロセン;TBDMSOTf:tert−ブチルジメチルシリルトリフルオロメタンスルホナート;TBAF:フッ化テトラブチルアンモニウム;(Boc)2O:ジ−tert−ブチルジカルボナート;HATU:o−(7−アザベンゾトリアゾール−1−イル−N,N,N’,N’−テトラメチルウロニウムヘキサフルオロホスファート;DIEA: N,N−ジイソプロピルエチルアミン;eq.:当量;sat.aq.:飽和水溶液;RT:室温;min:分;h:時間;M:モル濃度;wt:重量;atm:気圧;NMR:核磁気共鳴;MS:質量分析;ES:エレクトロスプレー;RP−HPLC:逆相高圧液体クロマトグラフィー;SCX:陽イオン交換樹脂;tBuOH:tert−ブタノール;Xphos:2−ジシクロヘキシルホスフィノ−2’,4’,6’−トリイソプロピルビフェニル;及びTEA:トリエチルアミンである。
の化合物の加水分解と、それに続く、保護されたアンモニア誘導体を用いた還元的アミノ化により、調製することができる。
の化合物を、臭素化し、続いてアルコキシビニルスタンナンとスティルカップリングすることにより、調製することができる。
の化合物と反応させることにより、調製することができる。反応は一般に、NaHCO3のような塩基の存在下、かつiPrOHのような溶媒中、還流下で行なう。
の化合物をエステル化することにより調製することができる。反応は、RxOHを用いて、一般にはH2SO4のような酸の存在下、かつMeOHのような溶媒中、還流下で行なうことができる。
の化合物を、第一級アミンで還元的アミノ化することにより、調製することができる。
の化合物を、連続的な酸化及びエステル化することにより、調製することができる。
の化合物を、環化し、続いて保護基を除去することにより、調製することができる。反応は一般に、dppf、Pd(OAc)2のような触媒、KOtBu又はNaOtBuのような塩基の存在下で、約80℃において行なう。
の化合物と反応させることにより、調製することができる。反応は一般に、NaHMDSの存在下、THFのような溶媒中で、約0℃ないし室温において行なう。
の化合物と反応させることにより、調製することができる。反応は一般に、まず、MeOHのような溶媒中で、試薬を約24時間還流すること、次にMeONaのような塩及びトルエンのような溶媒を添加すること、そして反応混合物を還流することにより行なわれる。
の化合物の水素化と、それに続く環化により、調製することができる。水素化及び環化は、一般に、水素雰囲気下、パラジウム炭素のような触媒の存在下、MeOHのような溶媒中で、ほぼ室温において行なってもよい。
の化合物の環化により調製することができる。反応は、一般に、HATU及びDIEAのような環化剤の存在下、DMFのような溶媒中で、ほぼ室温において行なってもよい。
A及びDがNであり、かつB及びEがCHである、式Iの化合物の誘導体を合成するための方法を、スキーム1に示す。出発物質である6−アミノピリジン−2−カルボン酸を対応するエステルへ最初の変換することに続き、α−ブロモアセトフェノンと反応させることで、2−アリールイミダゾ[1,2−a]ピリジン環を生成させた。AcOH中でBr2を用いた3位の選択的臭素化に続き、Pd2(dba)3/P(tBu)3BF4を触媒系として用いて、得られた化合物とのスティルカップリングを行なった。7員のラクタム環は、Hg(AcO)2のような試薬を用いて、THF/H2O中で、40℃において、エノールエーテルを加水分解し、それに続き、NaBH3CNの存在下で適当な第一級アミンを用いた還元的アミノ化、及びイン・サイチュ(in situ)の環化により生成した。最後に、アミド基を脱保護して、所望の阻害剤を得た。
別の三環式スカフォールド(scaffold)を、2−アリールイミダゾ[1,2−a]ピリジン中間体から、スキーム2に記載したように調製することができる。イミダゾ[1,2−a]ピリジンを、DMF中のPOCl3で処理して、3位にカルバルデヒド基を導入した。適当な第一級アミンによる、NaBH3CNの存在下で、Ti(iPrO)4をルイス酸として使用した還元的アミノ化することにより、対応する第二級アミンを得て、これをイン・サイチュで環化して、6員のラクタム環を生成させた。スキーム1に記載したようにアミド基を脱保護して、所望の類似体を得た。
異なる複素環系である、インダゾールをもつ一連の関連類似体は、3−ブロモ−2−ブロモメチル安息香酸エステルから、トルエン中で0℃においてDIBAL−Hで処理することによりカルボン酸エステルを選択的に還元し、続いて、得られたベンジル型アルコールを、2,6−ルチジンを塩基として使用して、TBDMSOTfのような試薬で保護することにより調製することができる。インダゾールコアは、Org.Lett.2000年、第2巻、第4号、p.519に記載された方法に従い、すなわち、ブロモベンジル中間体を、NaHMDSのような塩基の存在下、THF中で、アリールヒドラジンと反応させ、続いて、Pd(OAc)2/dppfを触媒系として用いて分子内クロスカップリング反応を行なうことで得た。その保護されたヒドロキシル基は、TBAFを用いた脱保護反応、それに続く、MnO2及びNaClO2/NaH2PO4を用いたカルボン酸への連続的な酸化、及びその後の、インドメタンのような試薬をCs2CO3のような塩基の存在下で使用したエステル化により、カルボン酸エステルに変換した。三環式コアの形成は、スキーム1に記載したものと同様の合成的変換に従って行なった。次に、アミド基の脱保護反応により、A及びBがCHであり、かつD及びEがNである式の、所望の化合物を得た(スキーム3)。
A、D、及びEがCHであり、かつBがNである、インドリジン複素環コアをもつ、一連の三環式阻害剤は、2−ハロニコチニックエステルから、スキーム4に示したように調製することができる。保護されたプロパルギルアミンとのソノガシラカップリング、それに続く、H2雰囲気下でPd/Cを触媒として用いた三重結合の水素化、及びその後の環化反応により、6,7,8,9−テトラヒドロ−5H−ピリド[3,2−c]アゼピン−5−オンを合成した。この二環式中間体を、CH3ONaのような塩基の存在下、α−ブロモアセトフェノンで処理して、3,4−ジヒドロアゼピノ[3,4,5−hi]インドリジン−1(2H)−オンスカフォールドをもつ所望の化合物を生成させた。
アリール置換基をさらに操作することで、スキーム5に示した別の誘導体を調製することができる。例えば、アリール基がニトリル置換基をもつ場合、これを、HCO2H及び、触媒としてのPtO2を用いた水素化分解により、対応するカルバルデヒドに還元することができる。その後の、対応するアミンを用いた還元的アミノ化と、それに続くスキーム1に記載のアミド基の脱保護により、所望のベンジル型アミンを得た。
追加の誘導体は、これらの化合物を反応の後期における修飾によって調製することができ、例えば、アリール環中のニトリル基を、H2雰囲気下、(Boc)2Oの存在下で、PtO2のような試薬を用いて還元して、保護されたベンジル型第一級アミンとすることができる。得られたBoc保護されたアミンは、酸性条件において脱保護することができる。所望の第二級又は第三級アミンへの変換は、NaBH3CNの存在下で適当なアルデヒドを用いた還元的アミノ化によって達成し得る。
アリール基がカルボン酸エステル置換基をもつ場合、これを、DIBAL−Hのようなヒドリド試薬を用いた反応により、対応するベンジル型アルコールに還元することができる。メシラートのような誘導体の調製と、それに続く第一級又は第二級アミンのような対応する求核試薬を用いた処理により、ヒドロキシル基を変換することで、所望の化合物を得た(スキーム7)。
作業試薬
アッセイ緩衝液: 100mM トリスpH8、4mM MgCl2、4mM スペルミン、200mM KCl、0.04% ノニデットP−40。
酵素混合物: アッセイ緩衝液(12.5ul)、100mM DTT(0.5ul)、PARP−1(5nM、トレビゲン(Trevigen)4668−500−01)、H2O(35ulまで)。
ニコチンアミド−アデニンジヌクレオチド(NAD)/DNA混合物:[3H−NAD](250uCi/ml、0.4ul、パーキン・エルマー(Perkin−Elmer)NET−443H)、NAD(1.5mM、0.05ul、シグマ(SIGMA)N−1511)、ビオチニル化−NAD(250uM、0.03ul、トレビゲン 4670−500−01)、活性化仔ウシ胸腺(1mg/ml、0.05ul、アマシャム・バイオサイエンシズ(Amersham Biosciences) 27−4575)、H2O(10ulまで)。
展開混合物: 500mM EDTA中に溶解された、ストレプトアビジンSPAビーズ(5mg/ml、アマシャム・バイオサイエンシズ RPNQ0007)。
反応は、96ウェルマイクロプレート中で、最終体積50uL/ウェルで行う。5ulの5%DMSO/化合物溶液を添加し、酵素混合物(35ul)を添加し、NAD/DNA混合物(10uL)の添加により反応を開始し、そして室温で2時間インキュベートする。展開混合物(25ul)の添加により反応を停止し、そして室温で15分間インキュベートする。パッカード・トップ・カウント(Packard TOP COUNT)装置を用いて測定する。
ヒトPARP−1に対する阻害活性
基本原理
この研究は、ニック入りDNA(すなわち、活性化仔ウシ胸腺)の提示時の、hPARP1によるポリ(ADP−リボシル化)の阻害について、化合物の活性を測定するべく設計した。IC50は、成長しつつあるポリ−ADP−リボース(PAR)ポリマーへの[3H]−NADの取込みと、ポリマーに取り込まれた放射能のシンチレーションカウンティングによる検出とに注目する、TCAアッセイにおいて測定した。
96ウェルポリプロピレンマイクロプレートに、化合物の連続希釈(0.1nM−50nMの濃度範囲に10ポイント、5%DMSO、5ul)又は5%DMSOを準備した。酵素反応は、25mMトリス−HClpH8.0、1mM MgCl2、50mM KCl、1mMスペルミン、0.01% ノニデットP−40、1mM DTT、1ug/ml 活性化仔ウシ胸腺DNA(アマシャム・バイオサイエンシズ 27−4575)、及び1nM のヒトPARP−1酵素(トレビゲン 4668−500−01)の存在下で行なった。反応は、全反応体積50ul中で、1ug/ml 活性化仔ウシ胸腺DNA(アマシャム・バイオサイエンシズ 27−4575)、0.4ul(2.2x105DPM)の[3H]−NAD(250uCi/ml、パーキン・エルマー NET−443H)、及び1.5ul NAD(シグマ#N−1511)の添加により開始した。室温で2時間のインキュベートの後、反応をTCA(50ul、20%)及びNaPPi(20mM)の添加により停止し、そして氷上で10分間インキュベートした。得られた沈殿を、ユニフィルター(Unifilter)GF/Bマイクロプレート(パーキン・エルマー)で濾過し、そしてハーベスター・フィルターメイト(Harvester Filtermate)196(パーキン・エルマー)を用いて、2.5%TCAで4回洗浄した。50ulのマイクロシンチ(Microscint)20(パーキン・エルマー)を添加した後、PARPポリマー中に取り込まれた放射能の量を、各ウェルについて、パーキン・エルマー・トップ・カウント(Perkin Elmer Top Count)で読み取った。IC50は、濃度を増していく化合物の存在下で残留する酵素活性に基づき、ADAソフトウェアによる4Pロジスティックフィッティングを使用して計算した。
略号:
IMDM(イスコブ(Iscove)改変ダルベッコ培地);RPMI(ロズウェル・パーク記念研究所培地(Roswell Park Memorial Institute Media);MOI(感染多重度);GFP(緑色蛍光タンパク質);PBS(リン酸緩衝食塩水);FCS(ウシ胎児血清);及びDMEM(ダルベッコ改変イーグル培地)。
N−メチル[4−(6−オキソ−6,7,8,9−テトラヒドロ−2,7,9b−トリアザベンゾ[cd]アズレン−1−イル)フェニル]メタンアミニウムトリフルオロアセテート(A7)
H2SO4(3.0当量)を、MeOH中(0.3M)の6−アミノピリジン−2−カルボン酸の懸濁液に添加した。反応混合物を、20時間加熱還流した。冷却後、溶媒を真空中で減少させ、残渣を冷却した飽和NaHCO3水溶液に添加した。水相をDCM(2回)で抽出し、合わせた有機抽出物を食塩水で洗浄し、そして脱水した(Na2SO4)。溶媒を蒸発させて、標題化合物を白色固体として得て、これをさらに精製することなく、次の工程に使用した。
1H NMR(400MHz,DMSO−d6,300K)δ7.50(1H,t,J=7.8Hz),7.18(1H,d,J=7.3Hz),6.65(1H,d,J=8.3Hz),6.28(2H,bs),3.79(3H,s)。MS(ES+)C7H8N2O2要求値:152,実測値:153(M+H)+。
NaHCO3(1.0当量)を、i−PrOH中(0.5M)の(A1)の溶液に添加し、次に4−シアノフェナシルブロミド(1.2当量)を添加し、得られた反応混合物を室温で18時間攪拌し、次いで、18時間さらに加熱還流した。冷却後、溶媒を真空中で減少させ、そして残渣を、飽和NaHCO3水溶液とDCMとの間で分配した。水相を分離し、そしてDCMで数回抽出した。合わせた有機抽出物を、食塩水で洗浄し、そして脱水した(Na2SO4)。溶媒を蒸発させ、残渣を得て、これを熱EtOHで粉砕し、そして濾過して、標題化合物を黄色の固体として得た(31%)。
1H NMR(400MHz,DMSO−d6,300K)δ9.31(1H,s),8.26(2H,d,J=8.3Hz),8.00(1H,d,J=9.0Hz),7.91(2H,d,J=8.3Hz),7.85(1H,d,J=7.0Hz),7.45(1H,dd,J=9.0,7.0Hz),4.00(3H,s)。MS(ES+)C16H11N3O2要求値:277,実測値:278(M+H)+。
Br2(1.0当量)を、DCM/AcOH=1:1中(0.05M)の(A2)の溶液に、室温で滴下添加し、そして反応混合物を室温で2時間攪拌した。反応混合物を、飽和NaHCO3水溶液の添加によりクエンチした。水相を分離し、そしてDCMで数回抽出した。合わせた有機抽出物を、食塩水で洗浄し、そして脱水した(Na2SO4)。溶媒を蒸発させ、残渣を得て、これをシリカ上でのフラッシュカラムクロマトグラフィーにより、EtOAc/石油エーテルの、30:70から50:50までの勾配を用いて精製し、標題化合物を白色固体として得た(88%)。
1H NMR(400MHz,DMSO−d6,300K)δ8.24(2H,d,J=8.4Hz),8.00(2H,d,J=8.6Hz),7.93(1H,d,J=8.6Hz),7.55−7.45(2H,m),4.02(3H,s)。MS(ES+)C16H10BrN3O2要求値:355/357,実測値:356/358(M+H)+。
DCM中(0.1M)の(A3)の脱気された溶液に、Cs2CO3(1.1当量)、トリス(ジベンジリデンアセトン)ジパラジウム(0)(0.05当量)、トリ−t−ブチルホスホニウムテトラフルオロボラート(0.15当量)、及びトリブチル[(Z)−2−エトキシビニル]スタンナン(2.0当量)を、室温で添加し、そして反応混合物を70℃で12時間加熱した。冷却後、溶媒を真空中で減少させ、そして残渣を、飽和NaHCO3水溶液とDCMとの間で分配した。水相を分離し、そしてDCMで数回抽出した。合わせた有機抽出物を、食塩水で洗浄し、そして脱水した(Na2SO4)。溶媒を蒸発させ、残渣を得て、これをシリカ上でのフラッシュカラムにより、EtOAc/石油エーテルの、30:70から50:50までの勾配を用いて精製し、標題化合物を黄色の油として得た(74%)。これは位置異性体の混合物である(シス/トランス=4:1)。
1H NMR(300MHz,CDCl3,300K)δ8.10(2H,d,J=8.3Hz),7.90(1H,d,J=8.7Hz),7.70(2H,d,J=8.3Hz),7.40(1H,d,J=6.4Hz),7.35−7.25(1H,m),6.32(1H,d,J=6.7Hz),5.65(1H,d,J=6.4Hz),3.97(3H,s),3.74(2H,q,J=7.0Hz),1.03(3H,t,J=7.0Hz)。MS(ES+)C20H17N3O3要求値:347,実測値:348(M+H)+。
THF/H2O 9:1の混合物中(0.2M)の(A4)の攪拌された溶液を、Hg(OAc)2(1.5当量)で処理した。反応混合物を50℃で3時間攪拌した後、新たに調製した飽和KI水溶液を添加し、そして室温で10分間攪拌を継続した。次いで、反応混合物をEtOAcで抽出し、飽和Na2S2O4水溶液で洗浄し、そして脱水した(Na2SO4)。溶媒を蒸発させ、メチル2−(4−シアノフェニル)−3−(2−オキソエチル)イミダゾ[1,2−a]ピリジン−5−カルボキシラートを得て、これをさらに精製することなく次の工程に使用した。
MS(ES+)C18H13N3O3要求値:319,実測値:320(M+H)+。
1H NMR(600MHz,DMSO−d6,330K)δ7.96(2H,d,J=8.4Hz),7.93(2H,d,J=8.4Hz),7.85(1H,d,J=8.8Hz),7.80(1H,d,J=7.0Hz),7.45(1H;dd,J=9.0,7.0Hz),7.22(1H,d,J=8.0Hz),6.62(1H,d,J=2Hz),6.53(1H;dd,J=8.4,2.0Hz),4.73(2H;s),3.84(3H,s),3.77(3H,s),3.72−3.68(2H,m),3.46−3.42(2H,m)。MS(ES+)C26H22N4O3要求値:438,実測値:439(M+H)+。
HCO2H(水中80%溶液)/THF=2.5:1の溶媒混合物中(0.2M)の、(A5)及びPtO2(0.1当量)の懸濁液を、60℃で4時間加熱した。冷却後、触媒をセライトのパッドを通して濾過し、次いで溶媒を真空中で減少させ、残渣を飽和NaHCO3水溶液とDCMとの間で分配した。水相を分離し、そしてDCMで数回抽出した。合わせた有機抽出物を、食塩水で洗浄し、そして脱水した(Na2SO4)。溶媒を蒸発させ、標題化合物を得て、これをさらに精製することなく次の工程に使用した。
1H NMR(400MHz,CDCl3,300K)δ9.96(1H,s),7.78(2H,d,J=7.8Hz),7.85−7.78(3H,m),7.72(1H,d,J=8.6Hz),7.29(1H,d,J=7.8Hz),7.27−7.18(1H,m),6.50−6.40(2H,m),4.78(2H,s),3.79(3H,s),3.75(3H,s),3.70−3.60(2H,m),3.30−3.20(2H,m)。MS(ES+)C26H23N3O4要求値:441,実測値:442(M+H)+。
DCE中(0.1M)の(A6)の溶液に、Me2NH・HCl(8当量)及びZnCl2(0.5当量)を添加し、そして混合物を室温で12時間攪拌した。この溶液に、NaBH3CN(1.1当量)を添加し、そして攪拌を12時間継続した。反応混合物を、飽和NaHCO3水溶液の添加によりクエンチし、次に水相を分離し、そしてDCMで数回抽出した。合わせた有機抽出物を、食塩水で洗浄し、そして脱水した(Na2SO4)。溶媒を蒸発させ、残渣である7−(2,4−ジメトキシベンジル)−1−{4−[(メチルアミノ)メチル]フェニル}−8,9−ジヒドロ−2,7,9b−トリアザベンゾ[cd]アズレン−6(7H)−オンを得て、これをさらに精製することなく次の工程に使用した。
MS(ES+)C27H28N4O3要求値:456,実測値:457(M+H)+。
1H NMR(300MHz,CD3CN,300K)δ9.00(1H,bs),8.18(1H,d,J=8.4Hz),8.05(1H,d,J=6.7Hz),7.80−7.70(3H,m),7.78−7.58(3H,m),4.22(2H,s),3.60−3.50(2H,m),3.45−3.35(2H,m);2.71(3H,s)。MS(ES+)C18H18N4O要求値:306,実測値:307(M+H)+。
N−メチル[4−(5−オキソ−4,5−ジヒドロ−3H−1,4,8b−トリアザアセナフチレン−2−イル)フェニル]メタンアミニウムトリフルオロアセテート(B4)
POCl3(5.0当量)を、DMF中(0.1M)の実施例1、A2の溶液に、室温で添加した。反応混合物を、1時間加熱還流した。冷却後、反応混合物を、氷水の添加によりクエンチし、次いで水相を分離し、そしてDCMで数回抽出した。合わせた有機抽出物を、食塩水で洗浄し、そして脱水した(Na2SO4)。溶媒を蒸発させ、残渣を得て、これをシリカ上でのフラッシュカラムにより、EtOAc/石油エーテルの、40:60から70:30までの勾配を用いて精製し、標題化合物を黄色の粉末として得た(58%)。
1H NMR(400MHz,DMSO−d6,300K)δ9.80(1H,s),8.22−8.15(3H,m),8.04(2H,d,J=8.4Hz),7.87(1H,dd,J=8.8,7.0Hz),7.70(1H,d,J=7.0Hz),3.92(3H,s)。MS(ES+)C17H11N3O3要求値:305,実測値:306(M+H)+。
MeOH中(0.2M)の(B1)の溶液に、2,4−ジメトキシベンジルアミン(1.2当量)及びTi(iPrO)4(2.0当量)を添加し、そして反応混合物を室温で2時間攪拌した。次に、NaBH3CN(1.5当量)を添加し、そして攪拌を24時間継続した。溶媒を真空中で減少させ、そして残渣を、飽和NaHCO3とDCMとの間で分配した。水相を分離し、そしてDCMで数回抽出した。合わせた有機抽出物を、食塩水で洗浄し、そして脱水した(Na2SO4)。溶媒を蒸発させ、残渣を得て、これをシリカ上でのフラッシュカラムにより、EtOAc/石油エーテルの、50:50から70:30までの勾配を用いて精製し、標題化合物を黄色の粉末として得た(55%)。
1H NMR(600MHz,DMSO−d6,330K)δ7.94(2H,d,J=8.6Hz),7.90(2H,d,J=8.6Hz),7.72(1H,d,J=9.0Hz),7.47(1H,d,J=7.0Hz),7.35(1H,dd,J=8.4,7.0Hz),7.23(1H,d,J=8.3Hz),6.61(1H,d,J=2.0Hz),6.48(1H,dd,J=8.3,2.0Hz),5.38(2H,s),4.72(2H,s),3.86(3H,s),3.74(3H,s)。MS(ES+)C25H20N4O3要求値:424,実測値:425(M+H)+。
HCO2H(水中80%溶液)/THF=2.5:1の溶媒混合物中(0.2M)の、(B2)及びPtO2(0.1当量)の懸濁液を、60℃で4時間加熱した。冷却後、触媒をセライトのパッドを通して濾過し、次いで溶媒を真空中で減少させ、残渣を、飽和NaHCO3水溶液とDCMとの間で分配した。水相を分離し、そしてDCMで数回抽出した。合わせた有機抽出物を、食塩水で洗浄し、そして脱水した(Na2SO4)。溶媒を蒸発させ、標題化合物を得て、これをさらに精製することなく次の工程に使用した。
1H NMR(400MHz,DMSO−d6,300K)δ10.0(1H,s),8.00(4H,m),7.75(1H,d,J=9.0Hz),7.49(1H,d,J=7.0Hz),7.38(1H,dd,J=8.4,7.0Hz),7.23(1H,d,J=8.3Hz),6.61(1H,d,J=2.0Hz),6.48(1H,dd,J=8.3,2.0Hz),5.40(2H,s),4.71(2H,s),3.86(3H,s),3.73(3H,s)。MS(ES+)C25H21N3O4要求値:427,実測値:428(M+H)+。
DCE中(0.1M)の(B3)の溶液に、Me2NH・HCl(8当量)及びTi(iPrO)4(2.0当量)を添加し、そして混合物を室温で12時間攪拌した。この溶液に、NaBH3CN(1.1当量)を添加し、そして攪拌を12時間継続した。反応混合物を、飽和NaHCO3水溶液の添加によりクエンチし、次に水相を分離し、そしてDCMで数回抽出した。合わせた有機抽出物を、食塩水で洗浄し、そして脱水した(Na2SO4)。溶媒を蒸発させ、残渣である4−(2,4−ジメトキシベンジル)−2−{4−[(メチルアミノ)メチル]フェニル}−3,4−ジヒドロ−5H−1,4,8b−トリアザアセナフチレン−5−オンを得て、これをさらに精製することなく次の工程に使用した。
MS(ES+)C26H26N4O3要求値:442,実測値:443(M+H)+。
1H NMR(400MHz,DMSO−d6,300K)δ8.76(1H,bs),8.68(1H,s)7.86(2H,d,J=8.0Hz),7.68(1H,d,J=9.0Hz),7.57(2H,d,J=8.0Hz),7.37(1H,d,J=7.0Hz),7.30(1H,dd,J=9.0,7.0Hz),5.28(2H,s),4.17(2H,s),2.60(3H,s)。MS(ES+)C17H16N4O要求値:292,実測値:293(M+H)+。
N−メチル[4−(6−オキソ−3,4,5,6−テトラヒドロ−2H−アゼピノ[5,4,3−cd]インダゾール−2−イル)フェニル]メタンアミニウムトリフルオロアセテート(C14)
無水トルエン中(0.45M)のメチル3−ブロモ−2−(ブロモメチル)ベンゾアートの溶液を、無水トルエン中(0.9M)のDIBAL−H(2当量、トルエン中1M)の溶液に、0℃で滴下添加した。反応混合物を、0℃で2時間攪拌した。次に、反応混合物を1N HClの溶液を用いてpH1までクエンチし、そして混合物をEtOAcで抽出した。合わせた有機抽出物を、食塩水で洗浄し、そして脱水した(Na2SO4)。溶媒を蒸発させ、標題化合物を白色粉末として得て(96%)、これをさらに精製することなく次の工程に使用した。
1H NMR(300MHz,DMSO−d6,300K)δ7.66(1H,d,J=8.0Hz),7.56(1H,d,J=7.4Hz),7.32(1H,t,J=7.6Hz),5.51(1H,bt,J=5.4Hz),4.83(2H,s),4.70(2H,bd,J=4.6Hz)。
無水DCM中(1M)の(C1)の溶液に、0℃で、2,6−ルチジン(2当量)及びTBDMSOTf(1.5当量)を添加した。反応混合物を、室温で45分間攪拌した。次いで、得られた溶液を、水とEt2Oとの間で分配し、有機相を分離し、そして脱水した(Na2SO4)。溶媒を蒸発させ、残渣を得て、これをシリカ上でのフラッシュカラムクロマトグラフィーにより、ヘキサン及び石油エーテルを使用して精製し、標題化合物を無色の油として得た(93%)。
1H NMR(400MHz,CDCl3,300K)δ7.51(1H,d,J=7.8Hz),7.41(1H,d,J=7.6Hz),7.17(1H,t,J=7.8Hz),4.86(2H,s),4.74(2H,s),0.95(9H,s),0.13(6H,s)。
(4−シアノフェニル)ヒドラジン塩酸塩(1当量)を、NaHMDS(2当量、THF中1M)の溶液に、0℃で添加した。反応混合物を0℃で15分間、そして次に室温で1時間攪拌した。その後、溶液を0℃に冷却し、そして無水THF中(1M)の(C2)の溶液を添加した。氷浴を除去し、そして反応混合物を室温で1時間攪拌した。次いで、反応混合物をDCMで希釈し、飽和NaHCO3水溶液、食塩水で洗浄し、そして脱水した(Na2SO4)。溶媒を蒸発させ、残渣を得て、これをシリカ上でのフラッシュカラムクロマトグラフィー(EtOAc/石油エーテル 1:24)により精製して、標題化合物を黄色の粉末として得た(77%)。
1H NMR(600MHz,DMSO−d6,300K)δ7.62−7.60(3H,m),7.53(1H,d,J=7.7Hz),7.32(1H,t,J=7.9Hz),7.22(2H,d,J=9Hz),4.82(2H,s),4.77(2H,s),4.30(2H,s),0.90(9H,s),0.04(6H,s)。MS(ES+)C21H28BrN3OSi要求値:445/447,実測値:446/448(M+H)+。
無水トルエン中(0.28M)の(C3)の溶液に、ナトリウムtert−ブトキシド(1.5当量)を、続いてdppf(0.075当量)、及びPd(OAc)2(5%mol)を添加した。反応混合物を、80℃で35分間加熱した。冷却後、反応混合物をシリカゲルカラム上に直接負荷し、そしてシリカ上でのフラッシュカラムクロマトグラフィーにより(EtOAc/石油エーテル 1:9)精製し、標題化合物を黄色の粉末として得た(68%)。
1H NMR(300MHz,CDCl3,300K)δ8.59(1H,s),8.07(2H,d,J=8.7Hz),7.83(2H,d,J=8.5Hz),7.64(1H,d,J=8.7Hz),7.32−7.28(1H,m),7.05−7.03(1H,m),4.99(2H,s),0.96(9H,s),0.13(6H,s)。MS(ES+)C21H25N3OSi要求値:363,実測値:364(M+H)+。
TBAF(1.3当量、THF中1M)を、無水THF中(0.1M)の(C4)の溶液に滴下添加し、そして室温で1時間攪拌した。反応混合物をEtOAcで希釈し、1N HCl(2回)、飽和NaHCO3水溶液、食塩水で洗浄し、そして脱水した(Na2SO4)。溶媒を蒸発させて、標題化合物を得た(100%)。
1H NMR(300MHz,DMSO−d6,300K)δ9.33(1H,s),8.36(2H,d,J=8.5Hz),8.11(2H,d,J=8.2Hz),7.62(1H,d,J=8.5Hz),7.36(1H,t,J=7.3Hz),7.12(1H,d,J=6.6Hz),5.36(1H,bt,J=5.4Hz),4.84(2H,d,J=5.2Hz)。MS(ES+)C15H11N3O要求値:249,実測値:250(M+H)+。
無水DCM中(0.07M)の(C5)の溶液に、酸化マンガン(IV)を添加した。反応混合物を、室温で2時間攪拌した。懸濁液を濾過し、そして沈殿をDCMで数回洗浄した。合わせた有機抽出物を、濃縮乾燥した。得られた粗生成物を、水/tert−ブタノール(1:1、0.04M)の混合物中に溶解した。その後、2−メチル−2−ブテン(20当量、THF中2M)、NaH2PO4(8当量)、及びNaClO2(8当量)を添加した。反応混合物を、室温で30分間攪拌した。次いで、混合物をDCM(3回)で抽出し、有機抽出物を食塩水(2回)で洗浄し、そして脱水した(Na2SO4)。溶媒を蒸発させ、標題化合物を黄色の粉末として得て、これをさらに精製することなく次の工程に使用した。
1H NMR(300MHz,DMSO−d6,300K)δ13.23(1H,bs),9.38(1H,s),8.45(2H,d,J=7.3Hz),8.12−8.09(3H,m),7.91(1H,d,J=6.8Hz),7.52(1H,t,J=7.0Hz)。MS(ES+)C15H9N3O2要求値:263,実測値:264(M+H)+。
Cs2CO3(1.2当量)を、無水DMF中(0.2M)の(C6)の溶液に添加した。得られた白色の懸濁液を、室温で30分間攪拌した。0℃に冷却後、ヨードメタン(7当量)を添加し、次いで、反応混合物を室温で90分間攪拌した。溶液をEtOAcで希釈し、食塩水(2回)で洗浄し、そして脱水した(Na2SO4)。溶媒を蒸発させ、標題化合物を得て、これをさらに精製することなく次の工程に使用した。
1H NMR(300MHz,CDCl3,300K)δ9.02(1H,s),8.14(2H,d,J=8.7Hz),8.01−7.95(2H,m),7.85(2H,d,J=8.5Hz),7.42(1H,t,J=7.4Hz),4.02(3H,s)。MS(ES+)C16H11N3O2要求値:277,実測値:278(M+H)+。
(C8)は、実施例1、工程3に報告した一般的な方法に従って調製し、そしてさらに精製することなく次の工程に使用した。
1H NMR(300MHz,CDCl3,300K)δ7.87−7.76(6H,m),7.43−7.38(1H,m),4.01(3H,s)。MS(ES+)C16H10BrN3O2要求値:355/357,実測値:356/358(M+H)+。
(C9)は、実施例1、工程4に報告した一般的な方法に従って調製し、そして標題化合物を黄色の油として得た(4工程で51%)。これは、単一の位置異性体(Z)である。
1H NMR(400MHz,CDCl3,300K)δ7.79−7.74(6H,m),7.36−7.32(1H,m),6.14(1H,d,J=7.1Hz),5.97(1H,d,J=6.8Hz),3.93(3H,s),3.53(2H,q,J=7.1Hz),0.90(3H,t,J=7.0Hz)。MS(ES+)C20H17N3O3要求値:347,実測値:348(M+H)+。
THF/H2Oの混合物中(9:1、0.2M)の、(C9)の攪拌された溶液を、Hg(OAc)2(1.2当量)で処理した。反応混合物を、室温で1時間攪拌した。反応を、新たに調製した飽和KI水溶液でクエンチし、得られた溶液を室温で10分間攪拌した。次に、混合物をEtOAcで抽出し、有機相を食塩水で洗浄し、そして脱水した(Na2SO4)。溶媒を蒸発させ、標題化合物を得て、これをさらに精製することなく次の工程に使用した。
1H NMR(400MHz,DMSO−d6,300K)δ9.74(1H,s),8.16(2H,d,J=8.6Hz),8.05(1H,d,J=8.1Hz),7.87(1H,d,J=7.1Hz),7.82(2H,d,J=8.6Hz),7.50(1H,d,J=7.1Hz),4.46(2H,s),3.90(3H,s)。MS(ES+)C18H13N3O3要求値:319,実測値:320(M+H)+。
無水EtOH中(0.16M)の(C10)の溶液に、2,4−ジメトキシベンジルアミン(1当量)を添加し、そして反応混合物を室温で1時間攪拌した。次に、NaBH3CN(1当量)を添加し、そして攪拌を12時間継続した。溶媒を減圧下で除去し、残渣をEtOAc中に溶解し、食塩水(2回)で洗浄し、そして脱水した(Na2SO4)。溶媒を蒸発させ、標題化合物を得て、これをさらに精製することなく次の工程に使用した。
MS(ES+)C27H26N4O4要求値:470,実測値:471(M+H)+。
無水MeOH中(0.2M)の(C11)の溶液に、K2CO3(1.1当量)を添加した。反応混合物を、マイクロウェーブ条件下で、120℃で3時間加熱した。溶媒を減圧下で除去し、そして残渣をEtOAc中に溶解した。得られた有機溶液を、食塩水(2回)で洗浄し、そして脱水した(Na2SO4)。溶媒を蒸発させ、残渣を得て、これをシリカ上でのフラッシュカラムクロマトグラフィー(EtOAc/石油エーテル 2:3)により精製し、標題化合物を得た(3工程で30%)。
1H NMR(400MHz,CDCl3,300K)δ8.04(1H,d,J=7.1Hz),7.89−7.77(5H,m),7.49(1H,dd,J=8.6及び7.1Hz),7.36(1H,d,J=8.6Hz),6.51−6.49(2H,m),5.00−4.75(2H,bs),3.84−3.79(8H,m),3.30−3.00(2H,bs)。MS(ES+)C26H22N4O3要求値:438,実測値:439(M+H)+。
(C13)は、実施例1、工程6に報告した一般的な方法に従い、0.2当量のPtO2を使用して調製した。この化合物を、さらに精製することなく次の工程に使用した。
1H NMR(400MHz,DMSO−d6,300K)δ10.16(1H,s),8.18(2H,d,J=8.6Hz),8.05(2H,d,J=8.4Hz),7.94(1H,d,J=8.6Hz),7.85(1H,d,J=6.8Hz),7.54(1H,dd,J=8.6及び7.1Hz),7.20(1H,d,J=8.3Hz),6.65(1H,d,J=2.3Hz),6.55(1H,dd,J=8.3及び2.3Hz),4.74(2H,bs),3.87(3H;s),3.81(3H;s),3.78−3.75(4H,m)。MS(ES+)C26H23N3O4要求値:441,実測値:442(M+H)+。
(C14)は、実施例1、工程7に報告した一般的な方法に従って調製し、標題化合物を淡黄色の粉末として得た(3工程で3%)。
1H NMR(600MHz,DMSO−d6,300K)δ8.89(2H,bs),8.31(1H,t,J=5.6Hz),7.92−7.90(3H,m),7.78(1H,d,J=7.0Hz),7.74(2H,d,J=8.4Hz),7.50(1H,dd,J=8.5及び7.0Hz),4.32−4.28(2H,m),3.53(2H,q,J=5.3Hz),3.32−3.27(2H,m);2.69−2.65(3H,m)。MS(ES+)C18H18N4O要求値:306,実測値:307(M+H)+。
N,N−ジメチル[4−(6−オキソ−3,4,5,6−テトラヒドロ−2H−アゼピノ[5,4,3−cd]インダゾール−2−イル)フェニル]メタンアミニウムトリフルオロアセテート(D1)
PtO2(0.5当量)を、MeOH中の、実施例3、(C12)及び(Boc)2O(1.5当量)の溶液に添加し、そして反応混合物を、50psiの圧力でパール装置に12時間取り付けた。次に、反応混合物を濾過し、溶媒を減圧下で蒸発させ、粗生成物を得て、これをEtOAc中に溶解し、食塩水で洗浄し、そして脱水した(Na2SO4)。溶媒を除去し、残渣であるtert−ブチル{4−[5−(2,4−ジメトキシベンジル)−6−オキソ−3,4,5,6−テトラヒドロ−2H−アゼピノ[5,4,3−cd]インダゾール−2−イル]ベンジル}カルバメートを得て、これをさらに精製することなく使用した。
MS(ES+)C31H34N4O5要求値:542,実測値:543(M+H)+。
MS(ES+)C17H16N4O要求値:292,実測値:293(M+H)+。
1H NMR(400MHz,CD3CN,300K)δ12.10(1H,bs),7.78(1H,d,J=8.6Hz),7.75(1H,d,J=7.0Hz),7.69−7.63(4H,m),7.40−7.36(1H,m),6.75(1H,bs),4.22(2H,s),3.54−3.48(2H,m),3.31−3.17(2H,m),2.70(6H,s)。MS(ES+)C19H20N4O要求値:320,実測値:321(M+H)+。
[4−(8−フルオロ−6−オキソ−3,4,5,6−テトラヒドロ−2H−アゼピノ[5,4,3−cd]インダゾール−2−イル)フェニル]−N,N−ジメチルメタンアミニウムトリフルオロアセテート(E18)
濃H2SO4中(0.83M)の5−フルオロ−2−メチル安息香酸(マトリックス・サイエンティフィック(Matrix Scientific)から)の溶液を、−10℃に冷却した。次に、発煙濃HNO3(2当量)及び濃H2SO4(4当量)の混合物を、滴下添加した。完全に添加した後、混合物を0℃で1時間攪拌した。反応混合物を、氷/水上に注入し、10分間攪拌し、そして次にEtOAcで抽出した。合わせた有機層を、食塩水で洗浄し、脱水し(Na2SO4)、そして溶媒を真空中で除去して、標題化合物を黄色の固体として得て、これをさらに精製することなく次の工程に使用した。
1H NMR(300MHz,DMSO−d6,300K)δ13.86(1H,bs),8.09(1H,dd,J=8.0及び2.6Hz),7.90(1H,dd,J=8.7及び2.4Hz),2.50(3H,s)。
MeOH中(0.5M)の(E1)の溶液に、炭素上のPd(10wt%、0.2当量)を添加した。反応混合物にH2雰囲気を装備し、得られた懸濁液を室温で24時間攪拌した。沈殿を濾去し、そして濾液を蒸発乾燥し、標題化合物を褐色の粉末として得て、これをさらに精製することなく次の工程に使用した。
1H NMR(400MHz,DMSO−d6,300K)δ8.39(1H,bs),7.98(1H,dd,J=11.1及び2.8Hz),6.85(1H,dd,J=9.1及び2.8Hz),3.21(2H,s),2.19(3H,s)。
亜硝酸tert−ブチル(1.5当量)を、0℃に冷却された無水アセトニトリル中(0.2M)の無水CuBr2(1.1当量)のスラリーに添加した。次に、得られた暗緑色の混合物に、(E2)を添加した。0℃で2時間の攪拌後、反応混合物を室温に温め、そしてこの温度で一晩攪拌した。反応混合物を真空下で濃縮し、そして得られた残渣をEtOAc中に溶解した。有機相を、飽和NH4Cl水溶液、食塩水で洗浄し、そして脱水した(Na2SO4)。減圧下で溶媒を蒸発させ、標題化合物を得て、これをさらに精製することなく次の工程に使用した。
MS(ES−)C8H6BrFO2要求値:232/234,実測値:231/233(M−H)−。
K2CO3(1.2当量)を、DMF中(0.26M)の(E3)の溶液に添加し、得られた懸濁液を、室温で30分間攪拌した。次に、ヨードメタン(1.2当量)を添加し、そして反応混合物を室温で一晩攪拌した。溶液をEtOAcで希釈し、有機相を食塩水で洗浄し、そして脱水した(Na2SO4)。溶媒を真空中で除去し、残渣を得て、これをシリカ上でのフラッシュクロマトグラフィーカラム(EtOAc/石油エーテル 1:49)により精製し、標題化合物を黄色の油として得た(4工程で31%)。
1H NMR(400MHz,CDCl3,300K)δ7.74(1H,dd,J=8.4及び2.8Hz),7.60(1H,dd,J=7.3及び2.5Hz),3.95(3H,s),2.59(3H,s)。
CCl4中(0.28M)の、(E4)、NBS(1.2当量)、及び過酸化ベンゾイル(0.1当量)の懸濁液を、4.5時間加熱還流した。その後、反応混合物を0℃に冷却し、そして固体を濾過した。固体をEt2Oで洗浄し、濾液を1M Na2S2O3、食塩水で連続的に洗浄し、そして脱水した(Na2SO4)。溶媒を減圧下で蒸発させ、標題化合物を得て、これをさらに精製することなく次の工程に使用した。
1H NMR(400MHz,CDCl3,300K)δ7.63(1H,dd,J=8.6及び2.8Hz),7.52(1H,dd,J=7.4及び2.8Hz),5.10(2H,s),3.97(3H,s)。
無水トルエン中(0.72M)のDIBAL−H(2当量、トルエン中1M)の溶液を、0℃に冷却した。次に、無水トルエン中(0.45M)の(E5)の溶液を滴下添加し、得られた溶液を0℃で2時間攪拌した。反応溶液を、1N HClの溶液でクエンチし、そして粗生成物をEtOAcで抽出した。有機相を食塩水で洗浄し、そして脱水した(Na2SO4)。溶媒を蒸発乾燥して、[3−ブロモ−2−(ブロモメチル)−5−フルオロフェニル]メタノールを白色粉末として得て、これをDCM中(1M)に、0℃で溶解した。得られた溶液を、2,6−ルチジン(2当量)及びTBDMSTf(1.5当量)で処理した。反応混合物を、室温で45分間攪拌した。次に、得られた溶液を、水とEt2Oとの間で分配し、有機相を分離し、そして脱水した(Na2SO4)。溶媒を蒸発させ、残渣を得て、これをシリカ上でのフラッシュカラムクロマトグラフィーにより、ヘキサン及び石油エーテルを使用して精製し、標題化合物を無色の油として得た(83%)。
1H NMR(400MHz,CDCl3,300K)d7.15−7.12(2H,m),4.74(2H,s),4.53(2H,s),0.86(9H,s),0.04(6H,s)。
(E7)は、実施例3、工程3に報告した一般的な方法に従って調製し、標題化合物を黄色の粉末として得た。
1H NMR(400MHz,DMSO−d6,300K)δ7.56(2H,d,J=8.8Hz),7.50(1H,dd,J=8.2及び2.6Hz),7.28(1H,dd,J=10.0及び2.8Hz),7.18(2H,d,J=9.1Hz),4.77(2H,s),4.66(2H,s),4.27(2H,s),0.87(9H,s),0.03(6H,s)。MS(ES+)C21H27BrFN3OSi要求値:463/465,実測値:464/466(M+H)+。
(E8)は、実施例3、工程4に報告した一般的な方法に従って調製し、標題化合物を黄色の粉末として得た(2工程で42%)。
1H NMR(300MHz,CDCl3,300K)δ8.55(1H,s),8.03(2H,d,J=7.6Hz),7.82(2H,d,J=8.1Hz),7.21(1H,bd,J=9.7Hz),6.91(1H,bd,J=9.5Hz),4.97(2H,s),0.97(9H,s),0.14(6H,s)。MS(ES+)C21H24FN3OSi要求値:381,実測値:382(M+H)+。
(E9)は、実施例3、工程5に報告した一般的な方法に従って調製し、標題化合物を得た(100%)。
1H NMR(300MHz,DMSO−d6,300K)δ9.40(1H,s),8.34(2H,d,J=8.5Hz),8.12(2H,d,J=7.6Hz),7.36(1H,d,J=9.9Hz),7.03(1H,d,J=10.3Hz),5.56−5.53(1H,m),4.87(2H,d,J=5.0Hz)。MS(ES+)C15H10FN3O要求値:267,実測値:268(M+H)+。
(E10)は、実施例3、工程6に報告した一般的な方法に従って調製し、そしてさらに精製することなく次の工程に使用した。
1H NMR(300MHz,DMSO−d6,300K)δ13.62(1H,bs),9.44(1H,s),8.44(2H,d,J=8.7Hz),8.11(2H,d,J=8.5Hz),7.88(1H,d,J=9.5Hz),7.71(1H,d,J=9.7Hz)。MS(ES+)C15H8FN3O2要求値:261,実測値:262(M+H)+。
(E11)は、実施例3、工程7に報告した一般的な方法に従って調製し、そしてさらに精製することなく次の工程に使用した。
1H NMR(300MHz,CDCl3,300K)δ8.95(1H,s),8.05(2H,d,J=8.5Hz),7.78(2H,d,J=8.5Hz),7.68−7.66(1H,m),7.53−7.50(1H,m),3.96(3H,s)。MS(ES+)C16H10FN3O2要求値:295,実測値:296(M+H)+。
(E12)は、実施例3、工程8に報告した一般的な方法に従って調製し、そしてさらに精製することなく次の工程に使用した。
1H NMR(300MHz,CDCl3,300K)δ7.89−7.76(4H,m),7.62−7.49(2H,m),4.02(3H,s)。
(E13)は、実施例3、工程9に報告した一般的な方法に従って調製し、標題化合物を黄色の粉末として得た(4工程で6%)。
1H NMR(300MHz,CDCl3,300K)δ7.88−7.72(4H,m),7.55−7.45(2H,m),6.15(1H,d,J=6.8Hz),5.92(1H,d,J=6.8Hz),3.94(3H,s),3.55(2H,q,J=7.2Hz),0.91(3H,t,J=7.0Hz)。MS(ES+)C20H16FN3O3要求値:365,実測値:366(M+H)+。
(E14)は、実施例3、工程10に報告した一般的な方法に従って調製し、そしてさらに精製することなく次の工程に使用した。
1H NMR(300MHz,DMSO−d6,300K)δ9.72(1H,s),8.16(2H,d,J=8.3Hz),7.88−7.80(3H,m),7.69(1H,d,J=10.3Hz),4.45(2H,s),3.92(3H,s)。MS(ES+)C18H12FN3O3要求値:337,実測値:338(M+H)+。
(E15)は、実施例3、工程11に報告した一般的な方法に従って調製し、そしてさらに精製することなく次の工程に使用した。
MS(ES+)C27H25FN4O4要求値:488,実測値:489(M+H)+。
(E16)は、実施例3、工程12に報告した一般的な方法に従って調製し、標題化合物を得た(3工程で25%)。
1H NMR(400MHz,CDCl3,300K)δ7.84(3H,m),7.74(2H,d,J=8.8Hz),7.43(1H,dd,J=8.8及び2.0Hz),7.35(1H,d,J=9.1Hz),6.51−6.49(2H,m),5.00−4.75(2H,bs),3.87−3.80(8H,m),3.20−2.95(2H,bs)。MS(ES+)C26H21FN4O3要求値:456,実測値:457(M+H)+。
(E17)は、実施例3、工程13に報告した一般的な方法に従って調製し、そしてさらに精製することなく次の工程に使用した。
MS(ES+)C26H22FN3O4要求値:459,実測値:460(M+H)+。
(E18)は、実施例3、工程14に報告した一般的な方法に従って調製し、標題化合物を白色粉末として得た(2工程で2.5%)。
1H NMR(400MHz,DMSO−d6,300K)δ10.29(1H,bs),8.44(1H,bs),7.85(2H,d,J=7.6Hz),7.73(2H,d,J=7.8Hz),7.64(1H,d,J=9.4Hz),7.51(1H,d,J=9.8Hz),4.41(2H,s),3.49(2H,bs),3.27(2H,bs);2.78(6H,s)。MS(ES+)C19H19FN4O要求値:338,実測値:339(M+H)+。
3−[4−(8−フルオロ−6−オキソ−3,4,5,6−テトラヒドロ−2H−アゼピノ[5,4,3−cd]インダゾール−2−イル)フェニル]ピペリジニウムトリフルオロアセテート(F14);8−フルオロ−2−{4−[(3R)−ピペリジン−3−イル]フェニル}−2,3,4,5−テトラヒドロ−6H−アゼピノ[5,4,3−cd]インダゾール−6−オン(F15);及び8−フルオロ−2−{4−[(3S)−ピペリジン−3−イル]フェニル}−2,3,4,5−テトラヒドロ−6H−アゼピノ[5,4,3−cd]インダゾール−6−オン(F16)
MeOH中(0.2M)の3−(4−クロロフェニル)ピペリジンの溶液に、ベンズアルデヒド(2.1当量)を添加し、そして反応混合物を室温で1時間攪拌した。次に、これを0℃に冷却し、そしてNaBH3CN(3当量)を添加した。混合物を室温に温め、そして1時間攪拌した。溶媒を蒸発させ、残渣を得て、これを飽和NaHCO3水溶液とEtOAcとの間で分配し、有機相を分離し、そして脱水した(Na2SO4)。溶媒を蒸発させ、粗生成物を得て、これをシリカ上でのフラッシュクロマトグラフィーカラム(石油エーテル−EtOAc/石油エーテル 1:19)により精製し、標題化合物を黄色の粉末として得た(62%)。
1H NMR(300MHz,DMSO−d6,300K)δ7.36−7.17(9H,m),3.48(2H,s),2.87−2.68(3H,m),2.05−1.91(2H,m),1.86−1.75(1H,m),1.74−1.50(2H,m),1.48−1.3(1H,m)。MS(ES+)C18H20ClN要求値:285,実測値:286(M+H)+。
脱気されたtBuOH中(0.18M)の、(F1)、ベンゾフェノンヒドラゾン(1.8当量)、NaOH粉末(1.4当量)、Pd(AcO)2(0.05当量)、及びXPhos(0.1当量)の混合物を、アルゴン下で、室温で20分間攪拌し、そして次に80℃で3時間加熱した。冷却後、溶媒を蒸発させ、残渣を得て、これをDCM中に溶解し、飽和NH4Cl水溶液(2回)及び飽和NaHCO3(2回)で洗浄し、そして脱水した(Na2SO4)。溶媒を蒸発させ、粗生成物を得て、これをシリカ上でのフラッシュクロマトグラフィーカラム(EtOAc/石油エーテル 2:98−1:4)により精製して、標題化合物を黄色の泡沫として得た(90%)。
1H NMR(300MHz,DMSO−d6,300K)δ8.68(1H,s),7.67−7.49(3H,m),7.46−7.39(2H,m),7.37−7.25(10H,m),7.13(2H,d,J=8.3Hz),7.04(2H,d,J=8.3Hz),3.47(2H,s),2.92−2.75(2H,m),2.70−2.56(1H,m),2.06−1.86(2H,m),1.83−1.50(3H,m),1.48−1.32(1H,m)。MS(ES+)C31H31N3要求値:445,実測値:446(M+H)+。
EtOH/濃HCl中(1:10、0.8M溶液)の(F2)の懸濁液を、室温で一晩攪拌した。次いで、反応混合物をEt2O(3回)で抽出し、水相を減圧下で濃縮し、そして高真空ポンプ下で乾燥させて、標題化合物をベージュ色の固体として得た(80%)。
1H NMR(300MHz,DMSO−d6,300K)δ10.84(1H,s),10.16(3H,s),8.22(1H,s),7.66−7.55(2H,m),7.48−7.39(3H,m),7.15(2H,d,J=8.1Hz),6.95(2H,d,J=8.1Hz),4.28(2H,s),3.38−3.22(2H,m),3.20−3.06(1H,m),3.05−2.80(2H,m),2.04−1.76(3H,m),1.69−1.52(1H,m)。MS(ES+)C18H25Cl2N3要求値:281,実測値:282(M+H)+。
(F4)は、実施例3、工程3に報告した一般的な方法に従って、(E6)を(F3)と反応させることにより調製し、標題化合物を黄色の油として得た(73%)。
1H NMR(300MHz,CDCl3,300K)δ7.32−7.23(7H,m),7.17−7.09(4H,m),4.83(2H,s),4.52(2H,s),3.54(2H,s),3.32(2H,bs),3.00−2.90(2H,m),2.84−2.74(1H,m),2.05−1.89(3H,m),1.76−1.78(2H,m),1.47−1.38(1H,m),0.90(9H,s),0.04(6H,s)。MS(ES+)C32H43BrFN3OSi要求値:611/613,実測値:612/614(M+H)+。
(F5)は、実施例3、工程4に報告した一般的な方法に従って調製し、標題化合物を黄色の油として得た(60%)。
1H NMR(300MHz,CDCl3,300K)δ8.43(1H,s),7.76(2H,d,J=8.5Hz),7.38−7.32(6H,m),7.29−7.22(2H,m),6.88(1H,bd,J=9.8Hz),4.98(2H,s),3.56(2H,s),3.03−2.92(3H,m),2.13−1.94(3H,m),1.77−1.73(3H,m),0.97(9H,s),0.14(6H,s)。MS(ES+)C32H40FN3OSi要求値:529,実測値:530(M+H)+。
Pd(OH)/C(10wt%、0.1当量)を、EtOH中(0.1M)の、(F5)及び(Boc)2O(1.1当量)の溶液に添加し、反応混合物を、H2雰囲気下で、室温で10分間攪拌した。次いでこれを濾過し、溶媒を減圧下で除去し、残渣を得て、これをシリカ上でのフラッシュクロマトグラフィーカラム(EtOAc/石油エーテル 1:19)により精製し、標題化合物を白色の泡沫として得た(67%)。
1H NMR(300MHz,CDCl3,300K)δ8.45(1H,s),7.76(2H,d,J=8.3Hz),7.38(2H,d,J=8.5Hz),7.24−7.22(1H,m),6.89(1H,dd,J=9.9及び1.0Hz),4.98(2H,s),4.30−4.10(2H,m),2.90−2.70(3H,m),2.09−2.05(1H,m),1.81−1.62(3H,m),1.48(9H,s),0.97(9H,s),0.14(6H,s)。MS(ES+)C30H42FN3O3Si要求値:539,実測値:540(M+H)+。
(F7)は、実施例3、工程5に報告した一般的な方法に従って調製し、標題化合物を得た(100%)。
1H NMR(400MHz,CDCl3,300K)δ8.50(1H,s),7.78(2H,d,J=7.9Hz),7.35(2H,d,J=8.1Hz),7.26−7.24(1H,m,溶剤のシグナルとオーバーラップ),6.85(1H,d,J=9.6Hz),4.93(2H,s),4.30−4.20(1H,m),4.20−4.00(2H,m),2.80−2.70(3H,m),2.15−2.05(1H,m),1.80−1.70(1H,m),1.70−1.50(2H,m),1.48(9H,s)。MS(ES+)C24H28FN3O3要求値:425,実測値:426(M+H)+。
(F8)は、実施例3、工程6及び7に報告した一般的な方法に従って調製し、そしてシリカ上でのフラッシュカラムクロマトグラフィー(EtOAc/石油エーテル 2:3)により精製し、標題化合物を淡黄色の泡沫として得た(39%)。
1H NMR(400MHz,CDCl3,300K)δ8.88(1H,s),7.85(2H,d,J=8.1Hz),7.68(1H,d,J=9.2Hz),7.57(1H,d,J=9.0Hz),7.38(2H,d,J=8.3Hz),4.30−4.10(2H,m),3.99(3H,s),2.80−2.70(3H,m),2.15−2.00(1H,m),1.80−1.70(1H,m),1.70−1.50(2H,m),1.47(9H,s)。MS(ES+)C25H28FN3O4要求値:453,実測値:454(M+H)+。
(F8)を、実施例3、工程8に報告した一般的な方法に従って、Br2(1.2当量)で処理し、次に反応粗生成物を、DCMで希釈し(0.2M)、そしてBoc2O(1.0当量)及びTEA(1.0当量)で処理した。反応混合物を、室温で1時間攪拌した。溶媒を蒸発させ、残渣を得て、これをシリカ上でのフラッシュクロマトグラフィーカラム(EtOAc/石油エーテル 1:8−1:6)により精製し、標題化合物を白色固体として得た(66%)。
1H NMR(400MHz,CDCl3,300K)δ7.60−7.50(4H,m),7.48−7.41(2H,m),4.33−4.13(2H,m),4.04(3H,s),2.89−2.76(3H,m),2.16−2.05(1H,m),1.86−1.78(1H,m),1.75−1.61(2H,m),1.51(9H,s)。MS(ES+)C25H27BrFN3O4要求値:531/533,実測値:532/534(M+H)+。
(F10)は、実施例3、工程9に報告した一般的な実験の変法に従って調製し、ここでは、CsF(2.1当量)を、最初の反応混合物に添加した。処理の後、溶媒を蒸発させ、残渣を得て、これをシリカ上でのフラッシュクロマトグラフィーカラム(EtOAc/石油エーテル 1:10−1:3)により精製し、標題化合物を黄色の油として得た(84%)。
1H NMR(400MHz,CDCl3,300K)δ7.49(2H,d,J=7.5Hz),7.42(2H,d,J=8.8Hz),7.28(2H,d,J=7.9Hz),6.08(1H,d,J=6.4Hz),5.68(1H,d,J=6.6Hz),4.28−4.00(2H,m),3.86(3H,s),3.57−3.47(2H,m),2.79−2.64(3H,m),2.08−1.93(1H,m),1.76−1.68(1H,m),1.64−1.50(2H,m),1.41(9H,s),0.92(3H,d,J=7.0Hz)。MS(ES+)C29H34FN3O5要求値:523,実測値:524(M+H)+。
(F11)は、実施例3、工程10に報告した一般的な方法に従って調製し、そしてさらに精製することなく次の工程に使用した。
1H NMR(400MHz,DMSO−d6,300K)δ9.77(1H,s),7.86(1H,d,J=9Hz),7.70(1H,d,J=10.3Hz),7.63−7.50(4H,m),4.41(2H,s),4.15−4.00(2H,m),3.94(3H,s),2.97−2.78(3H,m),2.10−1.95(1H,m),1.86−1.74(1H,m),1.72−1.59(2H,m),1.48(9H,s)。MS(ES+)C27H30FN3O5要求値:495,実測値:496(M+H)+。
(F12)は、実施例3、工程11に報告した一般的な方法に従って調製した。溶媒を蒸発させ、残渣を得て、これをシリカ上でのフラッシュクロマトグラフィーカラム(EtOAc/石油エーテル 1:1、及びEtOAc)により精製し、標題化合物を黄色の固体として得た(2工程で61%)。
1H NMR(400MHz,CDCl3,300K)δ7.67(1H,d,J=9.4Hz),7.53(1H,d,J=8.1Hz),7.42(2H,d,J=7.7Hz),7.35(2H,d,J=7.4Hz),7.11(2H,d,J=8.1Hz),6.44(1H,d,J=8.4Hz),6.40(1H,s),4.35−4.05(4H,m),3.97(3H,s),3.81(3H,s),3.74(3H,s),3.70−3.61(2H,m),3.18−3.09(2H,m),2.88−2.72(3H,m),2.16−2.07(1H,m),1.85−1.76(1H,m),1.76−1.55(2H,m),1.48(9H,s)。MS(ES+)C36H43FN4O6要求値:646,実測値:647(M+H)+。
THF/H2O中(1:1、0.2M)の(F12)の溶液に、LiOH(1.5当量)を添加し、そして反応混合物を室温で5.5時間攪拌した。次に、反応混合物を、6N HClの添加によりクエンチし、水相を分離し、そしてDCMで数回抽出した。合わせた有機層を食塩水で洗浄し、そして脱水した(Na2SO4)。溶媒を蒸発乾燥し、(2−{4−[1−(tert−ブトキシカルボニル)ピペリジン−3−イル]フェニル}−3−{2−[(2,4−ジメトキシベンジル)アミノ]エチル}−6−フルオロ−2H−インダゾール−4−カルボン酸(MS(ES+)C35H41FN4O6要求値:632,実測値:633(M+H)+))を得て、これをDMF中(0.034M)に溶解した。得られた溶液を、HATU(1.0当量)及びDIEA(1.0当量)で処理した。反応混合物を、室温で1時間攪拌した。次に、得られた混合物を、1N HCl溶液とDCMとの間で分配した。水相を分離し、そしてDCMで数回抽出した。合わせた有機層を食塩水で洗浄し、そして脱水した(Na2SO4)。溶媒を蒸発させ、残渣を得て、これをシリカ上でのフラッシュクロマトグラフィーカラム(EtOAc/石油エーテル 3:7−1:1)により精製し、標題化合物を白色粉末として得た(2工程で53%)。
1H NMR(400MHz,CDCl3,300K)δ7.80(1H,d,J=9.8Hz),7.50(2H,d,J=7.6Hz),7.44(1H,d,J=9.2Hz),7.38(2H,d,J=8.1Hz),7.34(1H,d,J=8.8Hz),6.55−6.40(2H,m),4.90−4.70(2H,m),4.30−4.00(2H,m),3.82(6H,s),3.80−3.70(2H,m),3.20−3.00(2H,m),2.80−2.70(3H,m),2.10−2.00(1H,m),1.80−1.70(1H,m),1.70−1.60(2H,m),1.48(9H,s)。MS(ES+)C35H39FN4O5要求値:614,実測値:615(M+H)+。
(F13)を、実施例1、工程7に報告した一般的な方法に従って脱保護し、(F14)を白色粉末として得た(55%)。
1H NMR(400MHz,CD3CN,300K)δ9.10−8.70(2H,bs),7.70−7.60(3H,m),7.60−7.40(3H,m),7.00−6.90(1H,m),3.60−3.50(2H,m),3.50−3.40(2H,m),3.30−3.20(1H,m),3.20−3.10(2H,m),3.10−2.90(2H,m),2.10−2.00(3H,m),1.90−1.70(1H,m)。MS(ES+)C21H22FN4O要求値:364,実測値:365(M+H)+。
1H NMR(400MHz,DMSO−d6,300K)8.41(1H,t,J=5.5Hz),7.67−7.63(3H,m),7.53−7.46(3H,m),3.48(2H,bs),3.25(2H,bs),3.04−2.94(2H,m),2.76−2.70(1H,m),2.60−2.48(2H,m),1.96−1.90(1H,m),1.70−1.48(3H,m)。MS(ES+)C21H22FN4O要求値:364,実測値:365(M+H)+。
1H NMR(400MHz,DMSO−d6,300K)8.41(1H,t,J=5.5Hz),7.67−7.63(3H,m),7.53−7.46(3H,m),3.48(2H,bs),3.25(2H,bs),3.04−2.94(2H,m),2.76−2.70(1H,m),2.60−2.48(2H,m),1.96−1.90(1H,m),1.70−1.48(3H,m)。MS(ES+)C21H22FN4O要求値:364,実測値:365(M+H)+。
N2,N2−ジメチル−N−[4−(1−オキソ−1,2,3,4−テトラヒドロアゼピノ[3,4,5−hi]インドリジン−5−イル)フェニル]グリシンアミド(G7)
DCM中(3M)の、プロパルギルアミン及びトリエチルアミン(1.3当量)の溶液に、0℃で、DCM中(5M)のベンジルクロロホルマート(1.1当量)の溶液を滴下添加した。反応混合物を、室温で2時間攪拌した。溶媒を蒸発させた後、得られた残渣をシリカ上でのフラッシュカラムクロマトグラフィー(EtOAc/石油エーテル 1:10)により精製し、標題化合物を得た(56%)。
1H NMR(300MHz,CDCl3,300K)δ7.3(5H,s),5.29(2H,s),5.0(1H,bs),3.85(2H,d,J=3.3Hz),2.21(1H,m)。MS(ES+)C11H11NO2要求値:189,実測値:190(M+H)+。
Et2O中(1M)のCH2N2(4当量)の溶液を、THF中(0.5M)の2−ブロモニコチン酸の溶液に、室温で滴下添加した。反応混合物を室温で一晩攪拌し、次いでAcOH(4当量)の滴下添加によりクエンチした。有機相を水及び食塩水で洗浄し、そして脱水した(Na2SO4)。溶媒を蒸発させ、標題化合物を得て(75%)、これをさらに精製することなく次の工程に使用した。
1H NMR(300MHz,CDCl3,300K)δ8.47(1H,dd,J=4.8Hz,2.1Hz),8.07(1H,dd,J=7.8Hz,2.1Hz),7.35(1H,dd,J=7.5Hz,4.5Hz),3.93(3H,s)。
CuI(0.047当量)を、トリエチルアミン中(0.27M)の(G2)の攪拌された溶液に、室温で添加し、そして混合物を、N2流を15分間溶液に通すことによって脱気した。0℃に冷却後、(G1)(1.05当量)を、続いてジクロロビス(トリフェニルホスフィン)パラジウム(II)(0.023当量)を添加した。0℃で1時間攪拌後、反応混合物を室温に温め、そして次に、8時間さらに攪拌した。混合物を、セライトのパッドを通して濾過し、そして溶媒を真空中で除去した。次いで、残渣をシリカ上でのフラッシュカラムクロマトグラフィー(EtOAc/石油エーテル 2:1)により精製して、標題化合物を得た(86%)。
1H NMR(400MHz,DMSO−d6,300K)δ8.67(1H,s),8.20(1H,d,J=8.0Hz),7.31(6H,m),5.28(1H,bs),5.13(2H,s),4.31(2H,s),3.89(3H,s)。MS(ES+)C18H16N2O4要求値:324,実測値:325(M+H)+。
炭素上のPd(10wt%)を、MeOH中(0.2M)の(G3)の溶液に添加し、そして反応混合物をH2雰囲気下(1気圧)で、室温で18時間攪拌した。触媒を、セライトのパッドを通した濾過により除去し、得られた溶液を5時間加熱還流した。冷却後、溶媒を真空中で除去し、残渣をシリカ上でのフラッシュカラムクロマトグラフィー(DCM/MeOH 20:1)により精製して、標題化合物を得た(69%)。
1H NMR(300MHz,CDCl3,300K)δ8.68(1H,m),8.18(1H,m),7.50(1H,m),6.88(1H,s),3.15(4H,m),2.12(2H,m)。MS(ES+)C9H10N2O要求値:162,実測値:163(M+H)+。
MeOH中(0.33M)の、(G4)及び2−ブロモ−1−(4−ニトロフェニル)エタノン(1.17当量)の混合物を、24時間加熱還流した。冷却後、CH3ONa(4当量)及びトルエンを添加した。次に、反応混合物を24時間さらに加熱還流した。冷却後、溶媒を真空中で除去し、そして得られた残渣をシリカ上でのフラッシュカラムクロマトグラフィー(DCM/MeOH 200:1)により精製して、標題化合物を得た(22%)。
1H NMR(300MHz,DMSO−d6,300K)δ8.42(1H,d,J=6.9Hz),8.27(3H,m),8.02(1H,s),7.76(2H,d,J=8.1Hz),7.40(1H,d,J=6.6Hz),6.68(1H,t,J=6.9Hz),3.30(2H,m),3.04(2H,m)。MS(ES+)C17H13N3O3要求値:307,実測値:308(M+H)+。
EtOH/H2O中(0.013M)の、(G5)、鉄粉末(6当量)、及びNH4Cl(10当量)の懸濁液を、3時間加熱還流した。冷却後、触媒を濾過により除去した。得られた濾液を真空中で濃縮し、残渣を得て、これをシリカ上でのフラッシュカラムクロマトグラフィーにより精製し、標題化合物を黄色の固体として得た(81%)。
1H NMR(400MHz,CD3OD,300K)δ8.68(1H,d,J=6.8Hz),7.60(1H,s),7.45(1H,d,J=6.8Hz),7.25(2H,d,J=8.0Hz),6.82(2H,d,J=8.0Hz),6.56(1H,t,J=6.8Hz),3.52(2H,m),3.08(2H,m)。MS(ES+)C17H15N3O要求値:277,実測値:278(M+H)+。
DMF中(0.05M)の、(G6)、N,N−ジメチルグリシン(2当量)、HATU(0.15当量)、及びDIEA(3当量)の溶液を、室温で一晩攪拌した。反応混合物を真空中で濃縮し、残渣を得て、これをシリカ上でのフラッシュカラムクロマトグラフィーにより精製し、標題化合物を得た(18%)。
1H NMR(300MHz,CD3OD,300K)δ8.26(1H,d,J=6.8Hz),7.65(3H,m),7.48(3H,m),6.60(1H,t,J=7.2Hz),3.54(2H,bs),3.20(2H,s),3.12(2H,bs),2.41(6H,s)。MS(ES+)C21H22N4O2要求値:362,実測値:363(M+H)+。
Claims (18)
- 式I:
各aは、0、1、2、又は3であり;
各bは、1又は2であり;
各cは、独立して、0、1、2、3、4、5、又は6であり;
各dは、独立して、0又は1であり;
各eは、独立して、0又は1であり;
各fは、独立して、0又は1であり;
各gは、独立して、0、1、2、3、4、5、又は6であり;
各hは、独立して、0又は1であり;
jは、0、1、2、又は3であり;
A、B、D、及びEのうちの1つは、Nであり、かつその他は、独立して、N又は、場合によってC若しくはCHのいずれかであり、ただしDがNであるとき、A、B、及びEの少なくとも1つはNであり;
R1及びR2の各々は、独立して、水素又はC1−6アルキルであり;
各R3は、独立して、ヒドロキシ、ハロゲン、シアノ、C1−6アルキル、ハロC1−6アルキル、C1−6アルコキシ、又はハロC1−6アルコキシであり;
R4、R5、R7、及びR8の各々は、独立して、水素、C1−6アルキル、又はハロC1−6アルキルであり;
R6及びR9の各々は、独立して、水素、C1−6アルキル、又はC3−10シクロアルキルであり;
各R10は、独立して、水素、ヒドロキシ、シアノ、ハロゲン、C1−6アルキル、C2−10アルケニル、ハロC1−6アルキル、ヒドロキシC1−6アルキル、C1−6アルキルカルボニル、C1−6アルコキシ、ハロC1−6アルコキシ、C1−6アルコキシカルボニル、カルボキシ、ニトロ、又は環であり、該環は:C6−10アリール;C6−10アリールオキシ;C6−10アリールカルボニル;C3−10シクロアルキル;オキセタニル;アゼチジニル;5又は6員の飽和又は部分飽和複素環(これは、独立して、N、O、及びSから選択される1、2、又は3個のヘテロ原子を含有する);5員の芳香族複素環(これは、独立して、N、O、及びSから選択される1、2、3、又は4個のヘテロ原子を含有し、該ヘテロ原子のうち1個以下がO又はSである);6員の芳香族複素環(これは、1、2、又は3個のN原子を含有する);又は、7ないし15員の不飽和、部分飽和、又は飽和複素環(これは、独立して、N、O、及びSから選択される1、2、3、又は4個のヘテロ原子を含有する)であり;該環のいずれもが、独立して、(CH2)xR11から選択される1、2、又は3個の基で置換されていてもよく;
各xは、独立して、0、1、2、3、4、5、又は6であり;
各R11は、独立して、ヒドロキシ、オキソ、シアノ、ハロゲン、C1−6アルキル、C2−10アルケニル、ハロC1−6アルキル、C1−6アルキルカルボニル、C1−6アルコキシ、ハロC1−6アルコキシ、ヒドロキシC1−6アルキル、C1−6アルコキシカルボニル、カルボキシ、NRaRb、CONRaRb、S(O)rRc、又は環であり、該環は:C6−10アリール;C6−10アリールC1−6アルキル;オキセタニル;アゼチジニル;5、6、又は7員の飽和又は部分飽和複素環(これは、独立して、N、O、及びSから選択される1、2、又は3個のヘテロ原子を含有する);5員の芳香族複素環(これは、独立して、N、O、及びSから選択される1、2、3、又は4個のヘテロ原子を含有し、該ヘテロ原子のうち1個以下がO又はSである);6員の芳香族複素環(これは、1、2、又は3個の窒素原子を含有する);又は、7ないし10員の不飽和又は部分飽和複素環(これは、独立して、N、O、及びSから選択される1、2、3、又は4個のヘテロ原子を含有する)であり;該環のいずれもが、独立して、ヒドロキシ、シアノ、ハロゲン、C1−6アルキル、C1−6アルコキシ、C2−10アルケニル、ハロC1−6アルキル、アミノ、C1−6アルキルアミノ、及びジ(C1−6アルキル)アミノから選択される1、2、又は3個の基で置換されていてもよく;
Ra及びRbの各々は、独立して、水素、C1−6アルキル、C1−6アルキルカルボニル、ハロC1−6アルキル、ヒドロキシC1−6アルキル、S(O)rRc、又はS(O)rN(Rd)2であり;或いは、
Ra及びRbは、それらが結合するN原子と一緒になって、アゼチジニル環又は、5、6、又は7員の、飽和又は部分飽和複素環(これは、1、2、又は3個のN原子と、ゼロ又は1個のO原子とを含有する)を形成し、該環は、独立して、ヒドロキシ、シアノ、ハロゲン、C1−6アルキル、C1−6アルコキシ、C2−10アルケニル、及びハロC1−6アルキルから選択される1、2、又は3個の基で置換されていてもよく;
rは、0、1、又は2であり;
Rcは、C1−6アルキル、C6−10アリール、オキセタニル、アゼチジニル、5員の芳香族複素環(これは、独立して、N、O、及びSから選択される1、2、3、又は4個のヘテロ原子を含有し、該ヘテロ原子のうち1個以下がO又はSである);6員の芳香族複素環(これは、1、2、又は3個の窒素原子を含有する);又は、7ないし10員の不飽和又は部分飽和複素環(これは、独立して、N、O、及びSから選択される1、2、3、又は4個のヘテロ原子を含有する)であり;該環のいずれもが、独立して、ヒドロキシ、シアノ、ハロゲン、C1−6アルキル、C2−10アルケニル、及びハロC1−6アルキルから選択される1、2、又は3個の基で置換されていてもよく;
各Rdは、独立して、水素又はC1−6アルキルであり;
Yは、C6−10アリール、5員の不飽和複素環(これは、独立して、O、N、及びSから選択される1、2、3、又は4個のヘテロ原子を含有するが、該ヘテロ原子のうち1個以下がO又はSである);6員の不飽和複素環(これは、1、2、又は3個のN原子を含有する);又は、7ないし10員の不飽和複素環(これは、独立して、N、O、及びSから選択される1、2、3、又は4個のヘテロ原子を含有する)である]
の化合物、又はその薬学的に許容される塩、立体異性体、若しくは互変異性体。 - Yがフェニルである、上記請求項のいずれか1項に記載の化合物。
- aが、0又は1であり、かつR3が、ハロC1−6アルキル又はハロゲンである、上記請求項のいずれか1項に記載の化合物。
- R10が、ヒドロキシ、C1−6アルキル、C1−6アルコキシ、ニトロ、又は環であり、該環が:アゼチジニル;5又は6員の飽和又は部分飽和複素環(これは、独立して、N、O、及びSから選択される1、2、又は3個のヘテロ原子を含有する);6員の芳香族複素環(これは、1、2、又は3個のN原子を含有する);又は、7ないし10員の飽和又は部分飽和複素環(これは、独立して、N、O、及びSから選択される1、2、3、又は4個のヘテロ原子を含有する)であり;該環のいずれもが、独立して、(CH2)xR11から選択される1、2、又は3個の基で置換されていてもよい、上記請求項のいずれか1項に記載の化合物。
- xが0であり、かつR11は、C1−6アルキルである、上記請求項のいずれか1項に記載の化合物。
- R10が、メチル、イソプロピル、ジアゾニアスピロ[4.5]デカニル、メチルピペリジニル、エトキシ、ニトロ、ヒドロキシ、ピリジニル、ピロリジニル、アゼチジニル、メチルピペラジニル、又はピペリジニルである、上記請求項のいずれか1項に記載の化合物。
- 上記請求項のいずれか1項に記載の化合物、又はその薬学的に許容される塩、立体異性体、若しくは互変異性体を、薬学的に許容される担体と一緒に含んでなる医薬組成物。
- 同時の、別々の、又は連続した投与のための、請求項1ないし10のいずれか1項に記載の化合物、又はその薬学的に許容される塩、立体異性体、若しくは互変異性体と、抗癌剤との組合せ。
- 治療において使用するための、請求項1ないし10のいずれか1項に記載の化合物、又はその薬学的に許容される塩、立体異性体、若しくは互変異性体。
- ポリ(ADP−リボース)ポリメラーゼ(PARP)の阻害により改善可能な症状の、治療又は予防において使用するための、請求項1ないし10のいずれか1項に記載の化合物、又はその薬学的に許容される塩、立体異性体、若しくは互変異性体。
- 癌、炎症性疾患、再灌流損傷、虚血症状、卒中、腎不全、心臓血管疾患、心臓血管疾患以外の血管疾患、糖尿病、神経変性疾患、レトロウイルス感染症、網膜損傷、皮膚老化、又はUV誘導性皮膚損傷の、治療又は予防において使用するための、請求項1ないし10のいずれか1項に記載の化合物、又はその薬学的に許容される塩、立体異性体、若しくは互変異性体。
- 請求項14又は15において定義された治療に使用する医薬製造のための、請求項1ないし10のいずれか1項に記載の化合物、又はその薬学的に許容される塩、立体異性体、若しくは互変異性体の使用。
- 癌治療用の化学増感剤又は放射線増感剤としての、請求項1ないし10のいずれか1項に記載の化合物、又はその薬学的に許容される塩、立体異性体、若しくは互変異性体の使用。
- 癌、炎症性疾患、再灌流損傷、虚血症状、卒中、腎不全、心臓血管疾患、心臓血管疾患以外の血管疾患、糖尿病、神経変性疾患、レトロウイルス感染症、網膜損傷、皮膚老化、又はUV誘導性皮膚損傷を、治療又は予防する方法であって、請求項1に記載の化合物、又は請求項1に記載の化合物を含んでなる組成物の有効量を、それを必要とする患者に投与することを含んでなる前記方法。
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