JP7411315B2 - Stat3阻害剤 - Google Patents
Stat3阻害剤 Download PDFInfo
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- JP7411315B2 JP7411315B2 JP2020558021A JP2020558021A JP7411315B2 JP 7411315 B2 JP7411315 B2 JP 7411315B2 JP 2020558021 A JP2020558021 A JP 2020558021A JP 2020558021 A JP2020558021 A JP 2020558021A JP 7411315 B2 JP7411315 B2 JP 7411315B2
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- 125000004079 stearyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 239000003206 sterilizing agent Substances 0.000 description 1
- 235000003702 sterols Nutrition 0.000 description 1
- 150000003432 sterols Chemical class 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 125000005017 substituted alkenyl group Chemical group 0.000 description 1
- 125000004426 substituted alkynyl group Chemical group 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 150000003890 succinate salts Chemical class 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- IIACRCGMVDHOTQ-UHFFFAOYSA-N sulfamic acid Chemical class NS(O)(=O)=O IIACRCGMVDHOTQ-UHFFFAOYSA-N 0.000 description 1
- 150000003871 sulfonates Chemical class 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 239000002600 sunflower oil Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 150000003892 tartrate salts Chemical class 0.000 description 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 description 1
- 125000006092 tetrahydro-1,1-dioxothienyl group Chemical group 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000003039 tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000000147 tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000006090 thiamorpholinyl sulfone group Chemical group 0.000 description 1
- 125000006089 thiamorpholinyl sulfoxide group Chemical group 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 1
- 229940033663 thimerosal Drugs 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 229960004072 thrombin Drugs 0.000 description 1
- 201000002510 thyroid cancer Diseases 0.000 description 1
- 230000000451 tissue damage Effects 0.000 description 1
- 231100000827 tissue damage Toxicity 0.000 description 1
- 238000003354 tissue distribution assay Methods 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 1
- 210000003606 umbilical vein Anatomy 0.000 description 1
- ZDPHROOEEOARMN-UHFFFAOYSA-N undecanoic acid Chemical compound CCCCCCCCCCC(O)=O ZDPHROOEEOARMN-UHFFFAOYSA-N 0.000 description 1
- 125000002948 undecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229940070710 valerate Drugs 0.000 description 1
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 1
- 210000003556 vascular endothelial cell Anatomy 0.000 description 1
- 235000019871 vegetable fat Nutrition 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 230000029663 wound healing Effects 0.000 description 1
- 125000001834 xanthenyl group Chemical group C1=CC=CC=2OC3=CC=CC=C3C(C12)* 0.000 description 1
- 239000011787 zinc oxide Substances 0.000 description 1
Classifications
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/18—Sulfonamides
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/22—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms
- C07C311/29—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
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- A—HUMAN NECESSITIES
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- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
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- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/36—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids
- C07C303/40—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids by reactions not involving the formation of sulfonamide groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2602/00—Systems containing two condensed rings
- C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
- C07C2602/04—One of the condensed rings being a six-membered aromatic ring
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Description
本出願は、2018年4月19日出願の米国仮出願第62/659,872号、および2019年1月17日出願の米国仮出願第62/793,491号に基づく利益と優先権を主張するものであり、これらの内容は、その全体を参照することで本明細書に引用される。
本明細書中に引用される特許、特許出願、および刊行物はすべて、本明細書に記載される発明の日付の時点で当業者に公知の技術の状況を十分に記述するために、全体を参照することで本明細書に組み込まれる。
本発明は全体として、医薬品科学分野に関連する。より具体的に本発明は、STAT3を阻害するための医薬品として有用な化合物と組成物に関する。さらに具体的に本発明は、癌、慢性炎症、線維症などの疾病を処置するための方法における化合物およびその使用に関する。
喘息は、世界人口の10%に影響を及ぼすものであり、その有病率はここ10年にわたり増加している。Akinbami LJ,Moorman JE,Bailey C,Zahran HS,King M,Johnson CA,et al.,Trends in asthma prevalence,health care use,and mortality in the United States,2001-e2010,NCHS DATA BRIEF,No 94,HYATTSVILLE,MD:NATIONAL CENTER FOR HEALTH STATISTICS,2012を参照。喘息は、複数の変異体を伴う異種疾患であり、その中で最も広く認識されているものは、アトピー、好酸球増加症、およびステロイドへの応答を特徴とするTh2-表現型である。例えば、Fahy J.V.,Eosinophilic and neutrophilic inflammation in asthma:insights from clinical studies,PROC AM THORAC SOC 2009,6(3)256-9;Wenzel S.E.,Asthma:defining of the persistent adult phenotypes,LANCET 2006,368(9537):804-13;Lin T,Poon AH,Hamid Q.,Asthma phenotypes and endotypes,CURR OPIN PUML MED.2013,19(1):18-23を参照。しかし、患者の10%が、非アトピー性、好中球性、およびステロイド耐性である喘息のTh17-表現型を有しており(“Proceedings of the ATS workshop on refractory asthma:current understanding,recommendations,and unanswered questions,” AM J RESPIR CRIT CARE MED 2000;162(6):2341-51;Al-Ramili W,Prefontaine D,Chouiali F,Martin JG,Olivenstein R,Lemiere C,et al.,T(H)17-associated cytokines (IL-17A and IL-17F) in severe asthma,J ALLERGY CLIN IMMUNOL 2009;123(5):1185-7;McKinley L,Alcorn JF,Peterson A,Dupont RB,Kapadia S,Logar A,et al.,Th17 cells mediate steroid-resistant airway inflammation and airway hyperresponsiveness in mice,J IMMUNOL 2008;181(6):4089-97)、その結果、利用可能とされる有効な処置を欠いていることで罹患率と死亡率がより高くなっている。Al-Ramili W,Prefontaine D,Chouiali F,Martin JG,Olivenstein R,Lemiere C,et al.,T(H)17-associated cytokines (IL-17A and IL-17F) in severe asthma,J Allergy Clin Immunol 2009,123(5):1185-7;Newcomb DC,Peebles RS Jr.Th-17 mediated inflammation in asthma,Curr Opin Immunol 2013;25(6):755-60を参照。代わりの治療選択肢が、この患者亜集団に対して明らかに必要である。
湿疹性皮膚疾患の重度の負担、ならびに総合的およびアレルゲン特異的血清IgEの上昇にもかかわらず、臨床的な食物アレルギーおよびアナフィラキシーは、STAT3変異により引き起こされる常染色体優性ハイパーIgE症候群(AD-HIES)の患者において著しく減少している。STAT3を抑制させた肥満細胞は、近位FcεRIシグナル伝達の不足が原因で正常に脱顆粒することができない。Siegel,a.M.et alを参照。STAT3変異を抱える患者のアレルギー疾患の減少により、肥満細胞脱顆粒時のSTAT3シグナル伝達の役割が明らかになっている(THE JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY,132,1388-1396,doi:10.1016/j.jaci.2013.08.045 (2013))。STAT3依存性サイトカインIL-6が血管漏出を引き起こす可能性があること(Wei,L.H.et al.,The role of IL-6 trans-signaling in vascular leakage:implications for ovarian hyperstimulation syndrome in a murine model,THE JOURNAL OF CLINICAL ENDOCRINOLOGY AND METABOLISM,98,E472-484,doi:10.1210/jc.2012-3462 (2013))、およびSTAT3シグナル伝達がギャップ接合ダイナミクスに関与していること(Guy,S.,Geletu,M.,Arulanandam,R.& Raptis,L.,Stat3 and gap junctions in normal and lung cancer cells,CANCERS 6,646-662,doi:10.3390/cancers6020646 (2014))を考慮すると、損なわれたSTAT3機能は、アナフィラキシー中に生じる内皮透過性を防ぐこともできる。ヒスタミン誘導型アナフィラキシーは、STAT3変異体AD-HIESマウス、および小分子STAT3阻害を受けた野生型マウスにおいて鈍化された。同様に、ヒスタミンの皮膚プリック応答は、AD-HIES患者において減少した。AD-HIESを抱える、またはSTAT3阻害剤で処置された患者から誘導されるヒト臍帯静脈血管内皮細胞(HUVEC)は、治療すると、Srcを介して適切にシグナルを伝達することも、接着結合タンパク質血管内皮(VE)-カドヘリンとβ-カテニンをダウンレギュレートすることもできなかった。AD-HIES HUVECSにおけるSTAT3標的mir17-92発現の減少は、Srcを阻害するPTENの増加、およびβ-カテニン細胞ダイナミクスを調節するE2F1に関連していた。ゆえにSTAT3依存性転写活性は、内皮結合アーキテクチャと機能ダイナミクス、および透過性に重要な構成要素を調節する。STAT3の長期的な機能アブレーションにより付着結合部の血管媒介物質誘導型の溶解が予防される。このことは、アナフィラキシーなどの過剰な血管透過性の臨床疾病がSTAT3の小分子阻害を介して媒介可能であることを示唆している。
IBDは、潰瘍性大腸炎(UC)またはクローン病(CD)のいずれかとして提示される。UCおよびCDの病因は確立されていないが、様々な遺伝子が、ATG16L、NOD2/CARD15、IBD5、CTLA4、TNFSF15、JAK2、STAT3、IL23R、およびORMDL3を含むゲノムワイド関連研究(GWAS)においてIBDの危険因子に関係があるとされている。これらは、抗菌ペプチド、生得および適応免疫細胞機能、Th17細胞、調節T細胞(Treg)、およびサイトカイン(腫瘍壊死因子、インターロイキン17、23、12、22、およびIL-6)に関係する。これらサイトカインの多くが、STAT3を活性化する細胞表面受容体のリガンドとして機能する。3つの細胞系統、骨髄細胞、腸細胞、およびT細胞内のSTAT3は、マウスとヒトの大腸炎に寄与することが実証されているが(Takeda K,Clausen BE,Kaisho T,et al.,Enhanced Th1 activity and development of chronic enterocolitis in mice devoid of Stat3 in macrophages and neutrophils,IMMUNITY 1999,10:39-49;Atreya R,Mudter J,Finotto S,et al.,Blockade of interleukin 6 trans signaling suppresses T-cell resistance against apoptosis in chronic intestinal inflammation:evidence in crohn disease and experimental colitis in vivo,NAT MED 2000,6:583-8;Suzuki A,Hanada T,Mitsuyama K,et al.,CIS3/SOCS3/SSI3 plays a negative regulatory role in STAT3 activation and intestinal inflammation,J.EXP.MED.2001,193:471-81)、効果は対照的である。一方で、骨髄細胞(好中球およびマクロファージ)または腸細胞内のSTAT3の遺伝的欠失により、それぞれ慢性マウス大腸炎が生じ、またはマウスが実験的大腸炎の影響を受けやすくなった。Pickert G,Neufert C,Leppkes M,et al.,STAT3 links IL-22 signaling in intestinal epithelial cells to mucosal wound healing,THE JOURNAL OF EXPERIMENTAL MEDICINE,2009,206:1465-72を参照。ゆえに骨髄細胞および腸細胞内のSTAT3は、大腸炎を防ぐものと思われる。一方、マウスに対して行われた直近の研究では、浸潤性CD4+T細胞内内のSTAT3がアポトーシスを防ぐことが実証されており、アポトーシスは慢性腸炎症に寄与するものである(Atreya R,Neurath MF,Signaling molecules:the pathogenic role of the IL-6/STAT-3 trans signaling pathway in intestinal inflammation and in colonic cancer,CURR DRUG TARGETS 2008,9:369-74内で調査されている)。このことは、T細胞内のSTAT3の活性化が慢性大腸炎に不可欠であることを示している。
R1の各出現は独立して、水素、ハロゲン、シアノ、ニトロ、CF3、OCF3、ORa、SRa、C(=O)Ra、OC(=O)Ra、C(=O)ORa、NRbRc、NRbC(=O)Rc、C(=O)NRbRc、NRbC(=O)ORc、OC(=O)NRbRc、NRaC(=O)NRbRc、アルキル、アルケニル、シクロアルキル、随意に置換されたアリール、または随意に置換された複素環であり、
n1は0、1、2、3、または4であり、
R2の各出現は独立して、水素、ハロゲン、シアノ、ニトロ、CF3、OCF3、ORa、SRa、C(=O)Ra、OC(=O)Ra、C(=O)ORa、NRbRc、NRbC(=O)Rc、C(=O)NRbRc、NRbC(=O)ORc、OC(=O)NRbRc、NRaC(=O)NRbRc、アルキル、アルケニル、シクロアルキル、シクロアルケニル、随意に置換されたアリール、随意に置換されたアリールオキシ、または随意に置換された複素環であり、
n2は0、1、2、3、4、または5であり、
R3は、水素、ハロゲン、シアノ、ニトロ、CF3、OCF3、ORa、SRa、OC(=O)Ra、アルキル、アルケニル、シクロアルキル、または随意に置換されたアリールもしくはヘテロアリールであり、
R4は、水素、ハロゲン、シアノ、ニトロ、CF3、OCF3、ORa、SRa、NRbRc、OC(=O)Ra、アルキル、アルケニル、またはシクロアルキルであり、
R5、R6、およびR7の各出現は独立して、水素、ハロゲン、シアノ、ニトロ、CF3、OCF3、ORa、SRa、C(=O)Ra、OC(=O)Ra、C(=O)ORa、NRbRc、NRbC(=O)Rc、C(=O)NRbRc、NRbC(=O)ORc、OC(=O)NRbRc、NRaC(=O)NRbRc、アルキル、アルケニル、シクロアルキル、随意に置換されたアリール、または随意に置換された複素環であり、
n3は0、1、2、3、または4であり、ならびに
Ra、Rb、およびRcの各出現は独立して、水素、アルキル、シクロアルキル、アルケニル、シクロアルケニル、アルキニル、複素環、もしくはアリールであり、または前記RbとRcは、それらが結合する窒素原子と一体となって、1~4のヘテロ原子を含む複素環を随意に形成する。
R1の各出現は独立して、水素、ハロゲン、シアノ、ニトロ、CF3、OCF3、ORa、SRa、C(=O)Ra、OC(=O)Ra、C(=O)ORa、NRbRc、NRbC(=O)Rc、C(=O)NRbRc、NRbC(=O)ORc、OC(=O)NRbRc、NRaC(=O)NRbRc、アルキル、アルケニル、シクロアルキル、随意に置換されたアリール、または随意に置換された複素環であり、
n1は0、1、2、3、または4であり、
R2の各出現は独立して、水素、ハロゲン、シアノ、ニトロ、CF3、OCF3、ORa、SRa、C(=O)Ra、OC(=O)Ra、C(=O)ORa、NRbRc、NRbC(=O)Rc、C(=O)NRbRc、NRbC(=O)ORc、OC(=O)NRbRc、NRaC(=O)NRbRc、アルキル、アルケニル、シクロアルキル、シクロアルケニル、随意に置換されたアリール、随意に置換されたアリールオキシ、または随意に置換された複素環であり、
n2は0、1、2、3、4、または5であり、
R3は、水素、ハロゲン、シアノ、ニトロ、CF3、OCF3、ORa、SRa、OC(=O)Ra、アルキル、アルケニル、シクロアルキル、または随意に置換されたアリールもしくはヘテロアリールであり、
R4は、水素、ハロゲン、シアノ、ニトロ、CF3、OCF3、ORa、SRa、NRbRc、OC(=O)Ra、アルキル、アルケニル、またはシクロアルキルであり、
R5、R6、およびR7の各出現は独立して、水素、ハロゲン、シアノ、ニトロ、CF3、OCF3、ORa、SRa、C(=O)Ra、OC(=O)Ra、C(=O)ORa、NRbRc、NRbC(=O)Rc、C(=O)NRbRc、NRbC(=O)ORc、OC(=O)NRbRc、NRaC(=O)NRbRc、アルキル、アルケニル、シクロアルキル、随意に置換されたアリール、または随意に置換された複素環であり、
n3は0、1、2、3、または4であり、ならびに
Ra、Rb、およびRcの各出現は独立して、水素、アルキル、シクロアルキル、アルケニル、シクロアルケニル、アルキニル、複素環、もしくはアリールであり、または前記RbとRcは、それらが結合する窒素原子と一体となって、1~4のヘテロ原子を含む複素環を随意に形成する。
本明細書で使用される用語の定義を以下に示す。本明細書中の群または用語に提供される最初の定義は、別段の指示がない限り、個別に、または別の群の一部として本明細書全体にわたる群または用語に適用される。別段の定めがない限り、本明細書で使用される技術用語と科学用語はすべて、当業者により一般に理解されるものと同じ意味を有する。
一態様では、式Iの化合物、
R1の各出現は独立して、水素、ハロゲン、シアノ、ニトロ、CF3、OCF3、ORa、SRa、C(=O)Ra、OC(=O)Ra、C(=O)ORa、NRbRc、NRbC(=O)Rc、C(=O)NRbRc、NRbC(=O)ORc、OC(=O)NRbRc、NRaC(=O)NRbRc、アルキル、アルケニル、シクロアルキル、随意に置換されたアリール、または随意に置換された複素環であり、
n1は0、1、2、3、または4であり、
R2の各出現は独立して、水素、ハロゲン、シアノ、ニトロ、CF3、OCF3、ORa、SRa、C(=O)Ra、OC(=O)Ra、C(=O)ORa、NRbRc、NRbC(=O)Rc、C(=O)NRbRc、NRbC(=O)ORc、OC(=O)NRbRc、NRaC(=O)NRbRc、アルキル、アルケニル、シクロアルキル、シクロアルケニル、随意に置換されたアリール、随意に置換されたアリールオキシ、または随意に置換された複素環であり、
n2は0、1、2、3、4、または5であり、
R3は、水素、ハロゲン、シアノ、ニトロ、CF3、OCF3、ORa、SRa、OC(=O)Ra、アルキル、アルケニル、シクロアルキル、または随意に置換されたアリールもしくはヘテロアリールであり、
R4は、水素、ハロゲン、シアノ、ニトロ、CF3、OCF3、ORa、SRa、NRbRc、OC(=O)Ra、アルキル、アルケニル、またはシクロアルキルであり、
R5、R6、およびR7の各出現は独立して、水素、ハロゲン、シアノ、ニトロ、CF3、OCF3、ORa、SRa、C(=O)Ra、OC(=O)Ra、C(=O)ORa、NRbRc、NRbC(=O)Rc、C(=O)NRbRc、NRbC(=O)ORc、OC(=O)NRbRc、NRaC(=O)NRbRc、アルキル、アルケニル、シクロアルキル、随意に置換されたアリール、または随意に置換された複素環であり、
n3は0、1、2、3、または4であり、ならびに
Ra、Rb、およびRcの各出現は独立して、水素、アルキル、シクロアルキル、アルケニル、シクロアルケニル、アルキニル、複素環、もしくはアリールであり、または前記RbとRcは、それらが結合する窒素原子と一体となって、1~4のヘテロ原子を含む複素環を随意に形成する。
略称
ACN アセトニトリル
EA 酢酸エチル
DMF ジメチルホルムアミド
PE 石油エーテル
DCM ジクロロメタン
THF テトラヒドロフラン
HOBT 1-ヒドロキシベンゾトリアゾール
EDCI 1-エチル-3-(3-ジメチルアミノプロピル)カルボジイミド
HBTU 2-(1H-ベンゾトリアゾール-1-イル)-1,1,3,3-テトラメチルウロニウムヘキサフルオロホスフェート
HATU N-[(ジメチルアミノ)(3H-1,2,3-トリアゾロ(4,4-b)ピリジン-3-イルオキシ)メチレン]-N-メチルメタンアミニウムヘキサフルオロホスフェート
PyBOP 1H-ベンゾトリアゾール-1-イルオキシトリピロリジノホスホニウムヘキサフルオロホスフェート
BOPCl ビス(2-オキソ-3-オキサゾリジニル)ホスフィンクロリド
BOP ベンゾトリアゾール-1-イルオキシトリス(ジエチルアミノ)ホスホニウムヘキサフルオロホスフェート
TEA トリエチルアミン
DIPEA ジイソプロピルエチルアミン
DMAP 4-ジメチルアミノピリジン
PCC クロロクロム酸ピリジニウム
PDC 二クロム酸ピリジニウム
NBS N-ブロモスクシンイミド
NCS N-クロロスクシンイミド
NIS N-ヨードスクシンイミド
9-BBN 9-ボラビシクロ[3.3.1]ノナン
TsOH p-トルエンスルホン酸
TFA トリフルオロアセトアミド
CDI カルボニルジイミダゾール
R1の各出現は独立して、水素、ハロゲン、シアノ、ニトロ、CF3、OCF3、ORa、SRa、C(=O)Ra、OC(=O)Ra、C(=O)ORa、NRbRc、NRbC(=O)Rc、C(=O)NRbRc、NRbC(=O)ORc、OC(=O)NRbRc、NRaC(=O)NRbRc、アルキル、アルケニル、シクロアルキル、随意に置換されたアリール、または随意に置換された複素環であり、
n1は0、1、2、3、または4であり、
R2の各出現は独立して、水素、ハロゲン、シアノ、ニトロ、CF3、OCF3、ORa、SRa、C(=O)Ra、OC(=O)Ra、C(=O)ORa、NRbRc、NRbC(=O)Rc、C(=O)NRbRc、NRbC(=O)ORc、OC(=O)NRbRc、NRaC(=O)NRbRc、アルキル、アルケニル、シクロアルキル、シクロアルケニル、随意に置換されたアリール、随意に置換されたアリールオキシ、または随意に置換された複素環であり、
n2は0、1、2、3、4、または5であり、
R3は、水素、ハロゲン、シアノ、ニトロ、CF3、OCF3、ORa、SRa、OC(=O)Ra、アルキル、アルケニル、シクロアルキル、または随意に置換されたアリールもしくはヘテロアリールであり、
R4は、水素、ハロゲン、シアノ、ニトロ、CF3、OCF3、ORa、SRa、NRbRc、OC(=O)Ra、アルキル、アルケニル、またはシクロアルキルであり、
R5、R6、およびR7の各出現は独立して、水素、ハロゲン、シアノ、ニトロ、CF3、OCF3、ORa、SRa、C(=O)Ra、OC(=O)Ra、C(=O)ORa、NRbRc、NRbC(=O)Rc、C(=O)NRbRc、NRbC(=O)ORc、OC(=O)NRbRc、NRaC(=O)NRbRc、アルキル、アルケニル、シクロアルキル、随意に置換されたアリール、または随意に置換された複素環であり、
n3は0、1、2、3、または4であり、ならびに
Ra、Rb、およびRcの各出現は独立して、水素、アルキル、シクロアルキル、アルケニル、シクロアルケニル、アルキニル、複素環、もしくはアリールであり、または前記RbとRcは、それらが結合する窒素原子と一体となって、1~4のヘテロ原子を含む複素環を随意に形成する。
また別の態様では、細胞中のSTAT3を阻害する方法が記載され、該方法は、本明細書に記載される実施形態のいずれか1つ以上に記載の少なくとも1つの化合物またはその薬学的に許容可能な塩の有効量を前記細胞に送達する工程を含む。
luminexビーズ、イムノブロッティング、またはelizaにより細胞の溶解物中の、または腫瘍サンプルの周辺血単核細胞および腫瘍細胞株(kasumi-1)の免疫組織化学により組織のスライド中のPY-STAT3分析物を測定するために、STAT3細胞阻害は、PY-STAT3抗体を使用して分析されてもよい。
本発明はまた、本明細書に記載される化合物の少なくとも1つ、またはその薬学的に許容可能な塩もしくは溶媒和物と、薬学的に許容可能な担体とを含む医薬組成物を提供する。
本発明のいくつかの態様は、特定の成果を達成するために有効量の組成物を被験体に投与する工程を含む。ゆえに、本発明の方法に係る有用な小分子組成物は、医薬用途に適した任意の様式で製剤することができる。
以下の代表的な実施例は、本発明の説明を助けることを目的としており、本発明の範囲を制限するように意図されるものでも、解釈されるものでもない。実際に、本明細書に示されかつ記述されるものに加えて、本発明およびその多くのさらなる実施形態に対する様々な変更は、付随する例や、本明細書で引用される科学文献および特許文献への言及を含む、本明細書の完全な内容から当業者には明白となるであろう。さらに、これら引用文献の内容は、当該技術分野の状況の記述を助けるために参照により本明細書に引用されるものであることを理解されたい。以下の実施例は、様々な実施形態およびその等価物において本発明の実施に適合可能である、重要な追加情報、例示、および指針を含む。
工程1:スルホンアミド-ナフトールの形成
Claims (14)
- (a)式IIIの化合物、
またはその薬学的に許容可能な塩、および
(b)薬学的に許容される担体または希釈剤、
を含む、医薬組成物。 - 被験体の高増殖性疾患または障害の処置に使用するための、請求項1に記載の医薬組成物。
- 前記高増殖性疾患が、頭頸部癌、肺癌、肝臓癌、乳癌、皮膚癌、腎臓癌、精巣癌、大腸癌、直腸癌、胃癌、転移性黒色腫、前立腺癌、卵巣癌、子宮頸癌、骨癌、脾臓癌、胆嚢癌、脳癌、膵臓癌、胃癌、肛門癌、前立腺癌、多発性骨髄腫、移植後リンパ増殖性疾患、再狭窄、骨髄異形成症候群、白血病、およびリンパ腫からなる群から選択される、請求項2に記載の医薬組成物。
- 前記高増殖性疾患が、頭頸部癌、肺癌、肝臓癌、乳癌、卵巣癌、大腸癌、多発性骨髄腫、白血病、および膵臓癌からなる群から選択される、請求項2に記載の医薬組成物。
- 被験体の線維症の処置に使用するための、請求項1に記載の医薬組成物。
- 前記線維症が、肺線維症、骨髄線維症、腸線維症、膵臓線維症、関節線維症、肝線維症、後腹膜線維症、骨髄線維症、真皮線維症、非アルコール性脂肪肝疾患、脂肪性肝炎、および全身性硬化症からなる群から選択される疾患または障害に関連する、請求項5に記載の医薬組成物。
- 前記線維症が、肺線維症、非アルコール性脂肪肝疾患、脂肪性肝炎、および全身性硬化症からなる群から選択される疾患または障害に関連する、請求項5に記載の医薬組成物。
- 被験体の炎症性疾患または障害の処置に使用するための、請求項1に記載の医薬組成物。
- 前記炎症性疾患または障害が、炎症性腸疾患、潰瘍性大腸炎、乾癬、ブドウ膜炎、胸膜炎、多発性硬化症、膵炎、および喘息からなる群から選択される、請求項8に記載の医薬組成物。
- 前記炎症性疾患または障害が、炎症性腸疾患、潰瘍性大腸炎、乾癬、および喘息からなる群から選択される、請求項8に記載の医薬組成物。
- 被験体の化学療法誘発末梢神経障害、糖尿病性神経障害、または家族性アミロイドポリニューロパチーの処置に使用するための、請求項1に記載の医薬組成物。
- 被験体の悪質液の処置に使用するための、請求項1に記載の医薬組成物。
- 被験体のアナフィラキシーの処置に使用するための、請求項1に記載の医薬組成物。
- 前記化合物が、シグナル伝達性転写因子3(STAT3)を阻害する、請求項2から13のいずれか1つに記載の医薬組成物。
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CN112367984A (zh) | 2021-02-12 |
US20240058284A1 (en) | 2024-02-22 |
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CN112367984B (zh) | 2024-05-10 |
US11826315B2 (en) | 2023-11-28 |
HUE059318T2 (hu) | 2022-11-28 |
DK3773537T3 (en) | 2022-04-25 |
IL278112A (ja) | 2020-12-31 |
SG11202010347XA (en) | 2020-11-27 |
AU2019255755A1 (en) | 2020-12-03 |
EP3773537B1 (en) | 2022-03-23 |
CA3097403A1 (en) | 2019-10-24 |
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