JP7345899B2 - リン酸塩誘導体およびその用途 - Google Patents
リン酸塩誘導体およびその用途 Download PDFInfo
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- JP7345899B2 JP7345899B2 JP2021501068A JP2021501068A JP7345899B2 JP 7345899 B2 JP7345899 B2 JP 7345899B2 JP 2021501068 A JP2021501068 A JP 2021501068A JP 2021501068 A JP2021501068 A JP 2021501068A JP 7345899 B2 JP7345899 B2 JP 7345899B2
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- 210000004985 myeloid-derived suppressor cell Anatomy 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000017074 necrotic cell death Effects 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 238000011580 nude mouse model Methods 0.000 description 1
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- 229960005019 pantoprazole Drugs 0.000 description 1
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- 108020003175 receptors Proteins 0.000 description 1
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- 230000002829 reductive effect Effects 0.000 description 1
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- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 235000020183 skimmed milk Nutrition 0.000 description 1
- RYYKJJJTJZKILX-UHFFFAOYSA-M sodium octadecanoate Chemical compound [Na+].CCCCCCCCCCCCCCCCCC([O-])=O RYYKJJJTJZKILX-UHFFFAOYSA-M 0.000 description 1
- 239000012439 solid excipient Substances 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 125000003003 spiro group Chemical group 0.000 description 1
- 210000000952 spleen Anatomy 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
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- 239000005720 sucrose Substances 0.000 description 1
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- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- PYFXOUCQTPUBOG-UHFFFAOYSA-N tert-butyl n-[1,3-dihydroxy-2-(hydroxymethyl)propan-2-yl]carbamate Chemical compound CC(C)(C)OC(=O)NC(CO)(CO)CO PYFXOUCQTPUBOG-UHFFFAOYSA-N 0.000 description 1
- YPNBMIQOTRHSDE-UHFFFAOYSA-J tetrasodium;dioxido-oxo-(2-phosphonatoethyl)-$l^{5}-phosphane Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]P([O-])(=O)CCP([O-])([O-])=O YPNBMIQOTRHSDE-UHFFFAOYSA-J 0.000 description 1
- 210000001685 thyroid gland Anatomy 0.000 description 1
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- 230000002588 toxic effect Effects 0.000 description 1
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- 230000001988 toxicity Effects 0.000 description 1
- 238000013519 translation Methods 0.000 description 1
- 230000008733 trauma Effects 0.000 description 1
- 230000004102 tricarboxylic acid cycle Effects 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- 230000005748 tumor development Effects 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
- 230000003827 upregulation Effects 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 230000007998 vessel formation Effects 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
- 238000005406 washing Methods 0.000 description 1
- 238000012447 xenograft mouse model Methods 0.000 description 1
Classifications
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/3804—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)] not used, see subgroups
- C07F9/3808—Acyclic saturated acids which can have further substituents on alkyl
- C07F9/3817—Acids containing the structure (RX)2P(=X)-alk-N...P (X = O, S, Se)
-
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- A61K31/66—Phosphorus compounds
- A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
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- A61K31/66—Phosphorus compounds
- A61K31/662—Phosphorus acids or esters thereof having P—C bonds, e.g. foscarnet, trichlorfon
- A61K31/663—Compounds having two or more phosphorus acid groups or esters thereof, e.g. clodronic acid, pamidronic acid
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- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- C07F9/3804—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)] not used, see subgroups
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- C07F9/3839—Polyphosphonic acids
- C07F9/3873—Polyphosphonic acids containing nitrogen substituent, e.g. N.....H or N-hydrocarbon group which can be substituted by halogen or nitro(so), N.....O, N.....S, N.....C(=X)- (X =O, S), N.....N, N...C(=X)...N (X =O, S)
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- C07F9/3882—Arylalkanephosphonic acids
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Description
本発明の一態様では、一般式(I)を有する化合物、またはその互変異性体、メソ体、ラセミ体、エナンチオマー、ジアステレオマー、またはその混合物形態、またはその薬学的に許容される塩、またはそのプロドラッグ(prodrug)分子であって、
Lは、C1-C10のアルキル基(alkyl group)、シクロアルキル基(cycloalkyl group)、シクロアルキルアルキル基(cycloalkylalkyl group)、アルキルシクロアルキル基(alkylcycloalkyl group)、アリール基(aryl group)、アリールアルキル基(arylalkyl group)、アルキルアリール基(alkylaryl group)、ヘテロアリール基(heteroaryl group)、ヘテロアリールアルキル基(heteroarylalkyl group)、アルキルヘテロアリール基(alkyl heteroaryl group)、アルケニル基(alkenyl group)、アルキニル基(alkynyl group)、NまたはOまたはS原子を含む3-15個の炭素原子直鎖または分岐鎖、NまたはOまたはS原子を含む1-15個の炭素原子直鎖または分岐鎖繰り返し単位の直鎖または分岐鎖、タンデムビスアリール基(tandem bisaryl group)、タンデムビスヘテロアリール基(tandem bisheteroaryl group)、タンデムアリール基(tandem aryl group)およびヘテロアリール基(heteroaryl group)、NまたはOまたはSまたは
を介して接続されるビスアリール基(bisaryl group)およびビスヘテロアリール基(bisheteroaryl group)から選択され、前記アルキル基、シクロアルキル基、ヘテロシクリル基(heterocyclic group)、アリール基またはヘテロアリール基は、それぞれ独立にヒドロキシ基(hydroxy group)、ハロゲン(halogen)、アルキル基、アルコキシ基(alkoxy group)、シクロアルキル基、ヘテロシクリル基(heterocyclic group)、アリール基およびヘテロアリール基から選択される1つまたは複数の置換基で置換されることができ、好ましくは、1つまたは複数の置換基を有するフェニル基(phenyl group)、ナフチル基(naphthyl group)であり、
R1およびR2は、それぞれ独立に水素、ハロゲン、アルキル基、シクロアルキル基、ヒドロキシアルキルヒドロカルビル基(hydroxyhydrocarbyl group)、アルコキシアルキル基(alkoxyalkyl group)、アルコキシシクロアルキル基(alkoxycycloalkyl group)、シクロアルキルアルキル基、アルキルシクロアルキル基(alkylcycloalkyl group)、アルケニル基、アルキニル基、アミノ基(amino group)、ヒドロキシ基、スルフヒドリル基(sulfhydryl group)、カルボキシ基(carboxy group)、アルコキシ基、シクロアルコキシ基、ハロアルキル基(haloalkyl group)、シアノ基(cyano group)、チオアルキル基(thioalkyl group)、スルフォ基(sulfo group)、スルホン基(sulfone group)、スルホキシド基(sulfoxide group)、ホスフェート基(phosphate group)、アルキルホスホン酸基(alkyl phosphonic acid group)、アリールホスフェート基(aryl phosphate group group)、アリールホスホン酸基(aryl phosphonic acid group)から選択され、前記アルキル基、シクロアルキル基、ヘテロシクリル基、アリール基またはヘテロアリール基は、それぞれ独立にヒドロキシ基、ハロゲン、アルキル基、アルコキシ基、シクロアルキル基、ヘテロシクリル基、アリール基およびヘテロアリール基から選択される1つまたは複数の置換基で置換されることができ、または空であり、
R3およびR4は、それぞれ独立に水素、アルキル基、シクロアルキル基、シクロアルキルアルキル基、アルキルシクロアルキル基、アリール基、アリールアルキル基、アルキルアリール基、ヘテロアリール基、ヘテロアリールアルキル基、アルキルヘテロアリール基、ヘテロシクリル基、ヘテロシクリルアルキル基(heterocyclyl alkyl group)、アルキルヘテロシクリル基(alkyl heterocyclyl group)、アルケニルアルキル基(alkenyl alkyl group)、アルキニルアルキル基(alkynyl alkyl group)から選択され、前記アルキル基、シクロアルキル基、シクロアルキルアルキル基、アルキルシクロアルキル基、アリール基、アリールアルキル基、アルキルアリール基、ヘテロアリール基、ヘテロアリールアルキル基、アルキルヘテロアリール基、ヘテロシクリル基、ヘテロシクリルアルキル基、アルキルヘテロシクリル基、アルケニルアルキル基、アルキニルアルキル基は、任意に非置換または1つまたは複数の置換基で置換され、前記置換基は、それぞれ独立にアルキル基、シクロアルキル基、シクロアルキルアルキル基、アルキルシクロアルキル基、アリール基、アリールアルキル基、アルキルアリール基、ヘテロアリール基、ヘテロアリールアルキル基、アルキルヘテロアリール基、ヘテロシクリル基、ヘテロシクリルアルキル基、アルキルヘテロシクリル基、アルケニル基、アルキニル基、アミノ基、ヒドロキシ基、スルフヒドリル基、カルボキシ基、アルコキシ基、シクロアルコキシ基、ハロアリール基(haloalkyl group)、アルコキシカルボニル基、アシルオキシ基(acyloxy group)、アミド基(amide group)、尿素基(urea group)、アルキルスルホニル基(alkylsulfonyl group)、芳香族スルホニル基、ハロアルキル基、ハロゲン、シアノ基、ニトロ基、ニトロソ基(nitroso group)、チオシアノ基(thiocyano group)、イソチオシアノ基(isothiocyano group)、チオアルキル基、スルフォ基、ホスフェート基、ホスホン酸基、アルキルホスフェート基(alkyl phosphate group)、アルキルホスホン酸基、アリールホスフェート基(aryl phosphate group)、アリールホスホン酸基から選択され、またはR3およびR4は、それらが結合しているN原子と一緒になって、単環式、二環式または三環式、または縮合環、架橋環またはスピロ環であるヘテロシクリル基を形成し、前記ヘテロシクリル基は、少なくとも1つのN原子を含み、またはN、SおよびOから任意に選択される1つまたは2つまたは3つのヘテロ原子を含み、前記ヘテロシクリル基は、非置換または1つまたは複数の置換基で置換され、前記置換基は、それぞれ独立にアルキル基、シクロアルキル基、シクロアルキルアルキル基、アルキルシクロアルキル基、アリール基、アリールアルキル基、アルキルアリール基、ヘテロアリール基、ヘテロアリールアルキル基、アルキルヘテロアリール基、ヘテロシクリル基、ヘテロシクリルアルキル基、アルキルヘテロシクリル基、アルケニル基、アルキニル基、アミノ基、ヒドロキシ基、スルフヒドリル基、カルボキシ基、アルコキシ基、シクロアルコキシ基、ハロアリール基、アルコキシカルボニル基、アシルオキシ基、アミド基、尿素基、アルキルスルホニル基、芳香族スルホニル基、ハロアルキル基、ハロゲン、シアノ基、ニトロ基、ニトロソ基、チオシアノ基、イソチオシアノ基、チオアルキル基、スルフォ基、ホスフェート基、ホスホン酸基、アルキルホスフェート基、アルキルホスホン酸基、アリールホスフェート基、アリールホスホン酸基を置換基として単独、または自由に組み合わせて形成された置換基から選択され、
A1、A2は、それぞれ独立にH、Li、Na、K、Csおよびそれらの対応するカチオンから選択され、またはA1、A2は一緒に、Ca、Mg、Al、Sc、Ti、Cr、Co、Fe、Ni、Cu、Zn、Cd、Hgおよびそれらのそれぞれの対応するカチオンを形成し、
Eは、O原子またはC(R1R2)から選択され、
R5、R6は、それぞれ独立に水素原子、ハロゲン、アルキル基、アルコキシアルキル基、シクロアルキル基、アルコキシシクロアルキル基、ヒドロキシアルキル基(hydroxyalkyl group)、ヒドロキシシクロアルキル基(hydroxycycloalkyl group)、ヘテロシクリル基、アリール基およびヘテロアリール基から選択され、前記アルキル基、シクロアルキル基、ヘテロシクリル基、アリール基またはヘテロアリール基は、それぞれ独立にヒドロキシ基、ハロゲン、アルキル基、アルコキシ基、シクロアルキル基、ヘテロシクリル基、アリール基およびヘテロアリール基から選択される1つまたは複数の置換基で置換されることができ、またはR5、R6は、3~8員環を形成することができ、前記環は、1~2個のO、N、および/またはSヘテロ原子を含むことができ、
R7、R8は、それぞれ独立に水素原子、アルキル基、ヒドロキシアルキル基、シクロアルキル基、アルコキシアルキル基、アルコキシシクロアルキル基、ヘテロシクリル基、アリール基およびヘテロアリール基から選択され、前記アルキル基、シクロアルキル基、ヘテロシクリル基、アリール基またはヘテロアリール基は、それぞれ独立にヒドロキシ基、ハロゲン、アルキル基、アルコキシ基、シクロアルキル基、ヘテロシクリル基、アリール基およびヘテロアリール基から選択される1つまたは複数の置換基で置換されることができ、
R9は、水素原子、ハロゲン、アルキルヒドロカルビル基、アルコキシアルキル基、シクロアルキル基、アルコキシシクロアルキル基、ヒドロキシアルキル基、ヒドロキシシクロアルキル基、ヘテロシクリル基、アリール基、ヘテロアリール基およびアシル基から選択され、前記アルキル基、アルコキシアルキル基、シクロアルキル基、アルコキシシクロアルキル基、ヒドロキシアルキル基、ヒドロキシシクロアルキル基、ヘテロシクリル基、アリール基、ヘテロアリール基およびアシル基は、それぞれ独立にヒドロキシ基、ハロゲン、アルキル基、アルコキシ基、シクロアルキル基、ヘテロシクリル基、アリール基およびヘテロアリール基から選択される1つまたは複数の置換基で置換されることができ、
R10は、水素原子、ハロゲン、アルキルヒドロカルビル基、シクロアルキル基、ヘテロシクリル基、アリール基、ヘテロアリール基から選択され、または空であり、前記アルキル基、シクロアルキル基、ヘテロシクリル基、アリール基またはヘテロアリール基は、それぞれ独立にヒドロキシ基、ハロゲン、アルキル基、アルコキシ基、シクロアルキル基、ヘテロシクリル基、アリール基およびヘテロアリール基から選択される1つまたは複数の置換基で置換されることができ、
R12は、水素原子、アルキルヒドロカルビル基、アルコキシアルキル基、シクロアルキル基、アルコキシシクロアルキル基、ヒドロキシアルキル基、ヒドロキシシクロアルキル基、ヘテロシクリル基、アリール基、ヘテロアリール基、ヘテロシクリルアルキル基、アリールアルキル基およびヘテロアリールアルキル基から選択され、前記アルキルヒドロカルビル基、アルコキシアルキル基、シクロアルキル基、アルコキシシクロアルキル基、ヒドロキシアルキル基、ヒドロキシシクロアルキル基、ヘテロシクリル基、アリール基、ヘテロアリール基、ヘテロシクリルアルキル基、アリールアルキル基およびヘテロアリールアルキル基は、それぞれ独立にヒドロキシ基、ハロゲン、アルキル基、アルコキシ基、シクロアルキル基、ヘテロシクリル基、アリール基およびヘテロアリール基から選択される1つまたは複数の置換基で置換されることができ、
n1は、1、2、3、4、5、6、7、8から選択され、
n2は、1、2、3、4、5、6から選択され、
n3は、1、2、3から選択され、
n4は、0、1、2、3、4から選択され、
n5は、0、1、2、3から選択され、
n6は、1、2、3から選択される、前記化合物を提供する。
Lは、C1-C10のアルキル基、シクロアルキル基、シクロアルキルアルキル基、アルキルシクロアルキル基、アリール基、アリールアルキル基、アルキルアリール基、ヘテロアリール基、ヘテロアリールアルキル基、アルキルヘテロアリール基、アルケニル基、アルキニル基、NまたはOまたはS原子を含む3-15個の炭素原子直鎖または分岐鎖、NまたはOまたはS原子を含む1-15個の炭素原子直鎖または分岐鎖繰り返し単位の直鎖または分岐鎖、タンデムビスアリール基、タンデムビスヘテロアリール基、タンデムアリール基およびヘテロアリール基、NまたはOまたはSまたは
を介して接続されるビスアリール基およびビスヘテロアリール基から選択され、前記アルキル基、シクロアルキル基、ヘテロシクリル基、アリール基またはヘテロアリール基は、それぞれ独立にヒドロキシ基、ハロゲン、アルキル基、アルコキシ基、シクロアルキル基、ヘテロシクリル基、アリール基およびヘテロアリール基から選択される1つまたは複数の置換基で置換されることができ、好ましくは1つまたは複数の置換基を有するフェニル基、ナフチル基であり、
R1およびR2は、それぞれ独立に水素、ハロゲン、アルキル基、シクロアルキル基、ヒドロキシアルキルヒドロカルビル基、アルコキシアルキル基、アルコキシシクロアルキル基、シクロアルキルアルキル基、アルキルシクロアルキル基、アルケニル基、アルキニル基、アミノ基、ヒドロキシ基、スルフヒドリル基、カルボキシ基、アルコキシ基、シクロアルコキシ基、ハロアルキル基、シアノ基、チオアルキル基、スルフォ基、スルホン基、スルホキシド基、ホスフェート基、アルキルホスホン酸基、アリールホスフェート基、アリールホスホン酸基から選択され、前記アルキル基、シクロアルキル基、ヘテロシクリル基、アリール基またはヘテロアリール基は、それぞれ独立にヒドロキシ基、ハロゲン、アルキル基、アルコキシ基、シクロアルキル基、ヘテロシクリル基、アリール基およびヘテロアリール基から選択される1つまたは複数の置換基で置換されることができ、
トリメチロールメチル基およびジメチロールアルキルメチル基(dimethylolalkylmethyl group)であり、
A1、A2は、それぞれ独立にH、Li、Na、K、Csおよびそれらの対応するカチオンから選択され、またはA1、A2は一緒に、Ca、Mg、Al、Sc、Ti、Cr、Co、Fe、Ni、Cu、Zn、Cd、Hgおよびそれらのそれぞれの対応するカチオンを形成し、
Eは、C(R1R2)から選択され、
R5、R6は、それぞれ独立に水素原子、ハロゲン、アルキル基、アルコキシアルキル基、シクロアルキル基、アルコキシシクロアルキル基、ヘテロシクリル基、アリール基およびヘテロアリール基から選択され、前記アルキル基、シクロアルキル基、ヘテロシクリル基、アリール基またはヘテロアリール基は、それぞれ独立にヒドロキシ基、ハロゲン、アルキル基、アルコキシ基、シクロアルキル基、ヘテロシクリル基、アリール基およびヘテロアリール基から選択される1つまたは複数の置換基で置換されることができ、またはR5、R6は、3~8員環を形成することができ、前記環は、1~2個のO、N、および/またはSヘテロ原子を含むことができ、
R7、R8は、それぞれ独立に水素原子、アルキル基、ヒドロキシアルキル基、シクロアルキル基、アルコキシアルキル基、アルコキシシクロアルキル基、ヘテロシクリル基、アリール基およびヘテロアリール基から選択され、前記アルキル基、シクロアルキル基、ヘテロシクリル基、アリール基またはヘテロアリール基は、それぞれ独立にヒドロキシ基、ハロゲン、アルキル基、アルコキシ基、シクロアルキル基、ヘテロシクリル基、アリール基およびヘテロアリール基から選択される1つまたは複数の置換基で置換されることができ、
R9は、水素原子、アルキル基、シクロアルキル基、ヘテロシクリル基、アリール基およびヘテロアリール基から選択され、前記アルキル基、シクロアルキル基、ヘテロシクリル基、アリール基またはヘテロアリール基は、それぞれ独立にヒドロキシ基、ハロゲン、アルキル基、アルコキシ基、シクロアルキル基、ヘテロシクリル基、アリール基およびヘテロアリール基から選択される1つまたは複数の置換基で置換されることができ、
R10は、水素原子、ハロゲン、アルキル基、シクロアルキル基、ヘテロシクリル基、アリール基、ヘテロアリール基から選択され、または空であり、前記アルキル基、シクロアルキル基、ヘテロシクリル基、アリール基またはヘテロアリール基は、それぞれ独立にヒドロキシ基、ハロゲン、アルキル基、アルコキシ基、シクロアルキル基、ヘテロシクリル基、アリール基およびヘテロアリール基から選択される1つまたは複数の置換基で置換されることができ、
n1は、0、1、2、3、4、5、6、7、8から選択され、
n2は、1、2、3、4、5、6から選択され、
n3は、1、2、3から選択され、
n4は、0、1、2、3、4から選択され、
n5は、0、1、2、3から選択され、
n6は、1、2、3から選択される。
R3およびR4は、それぞれ独立に水素、アルキル基、シクロアルキル基、シクロアルキルアルキル基、アルキルシクロアルキル基、アリール基、アリールアルキル基、アルキルアリール基、ヘテロアリール基、ヘテロアリールアルキル基、アルキルヘテロアリール基、ヘテロシクリル基、ヘテロシクリルアルキル基、アルキルヘテロシクリル基、アルケニル基、アルキニル基から選択され、前記アルキル基、シクロアルキル基、シクロアルキルアルキル基、アルキルシクロアルキル基、アリール基、アリールアルキル基、アルキルアリール基、ヘテロアリール基、ヘテロアリールアルキル基、アルキルヘテロアリール基、ヘテロシクリル基、ヘテロシクリルアルキル基、アルキルヘテロシクリル基、アルケニル基、アルキニル基は、任意に非置換または1つまたは複数の置換基で置換され、前記置換基は、それぞれ独立にアルキル基、シクロアルキル基、シクロアルキルアルキル基、アルキルシクロアルキル基、アリール基、アリールアルキル基、アルキルアリール基、ヘテロアリール基、ヘテロアリールアルキル基、アルキルヘテロアリール基、ヘテロシクリル基、ヘテロシクリルアルキル基、アルキルヘテロシクリル基、アルケニル基、アルキニル基、アミノ基、ヒドロキシ基、スルフヒドリル基、カルボキシ基、アルコキシ基、シクロアルコキシ基、ハロアリール基、アルコキシカルボニル基、アシルオキシ基、アミド基、尿素基、アルキルスルホニル基、芳香族スルホニル基、ハロアルキル基、ハロゲン、シアノ基、ニトロ基、ニトロソ基、チオシアノ基、イソチオシアノ基、チオアルキル基、スルフォ基、ホスフェート基、ホスホン酸基、アルキルホスフェート基、アルキルホスホン酸基、アリールホスフェート基、アリールホスホン酸基から選択され、またはR3およびR4は、それらが結合しているN原子と一緒になって、単環式、二環式または三環式、または縮合環、架橋環またはスピロ環であるヘテロシクリル基を形成し、前記ヘテロシクリル基は、少なくとも1つのN原子を含み、またはN、SおよびOから任意に選択される1つまたは2つまたは3つのヘテロ原子を含み、前記ヘテロシクリル基は、非置換または1つまたは複数の置換基で置換され、前記置換基は、それぞれ独立にアルキル基、シクロアルキル基、シクロアルキルアルキル基、アルキルシクロアルキル基、アリール基、アリールアルキル基、アルキルアリール基、ヘテロアリール基、ヘテロアリールアルキル基、アルキルヘテロアリール基、ヘテロシクリル基、ヘテロシクリルアルキル基、アルキルヘテロシクリル基、アルケニル基、アルキニル基、アミノ基、ヒドロキシ基、スルフヒドリル基、カルボキシ基、アルコキシ基、シクロアルコキシ基、ハロアリール基、アルコキシカルボニル基、アシルオキシ基、アミド基、尿素基、アルキルスルホニル基、芳香族スルホニル基、ハロアルキル基、ハロゲン、シアノ基、ニトロ基、ニトロソ基、チオシアノ基、イソチオシアノ基、チオアルキル基、スルフォ基、ホスフェート基、ホスホン酸基、アルキルホスフェート基、アルキルホスホン酸基、アリールホスフェート基、アリールホスホン酸基を置換基として単独、または自由に組み合わせて形成された置換基から選択される。
前記R11は、水素、ハロゲン、C1-C6アルキル基、C3-C8シクロアルキル基、ヒドロキシアルキルヒドロカルビル基、アルコキシアルキル基、アルコキシシクロアルキル基、シクロアルキルアルキル基、アルキルシクロアルキル基、アルケニル基、アルキニル基、アミノ基、ヒドロキシ基、アルコキシ基、シクロアルコキシ基、ハロアルキル基、シアノ基、チオアルキル基、スルフォ基、スルホン基、スルホキシド基、アリール基またはヘテロアリール基から選択され、前記アルキル基、シクロアルキル基、ヘテロシクリル基、アリール基またはヘテロアリール基は、それぞれ独立にヒドロキシ基、ハロゲン、アルキル基、アルコキシ基、シクロアルキル基、ヘテロシクリル基、アリール基およびヘテロアリール基から選択される1つまたは複数の置換基で置換されることができる。
R11は、水素、ハロゲン、C1-C6アルキル基、C3-C8シクロアルキル基、ヒドロキシアルキルヒドロカルビル基、アルコキシアルキル基、アルコキシシクロアルキル基、シクロアルキルアルキル基、アルキルシクロアルキル基、アルケニル基、アルキニル基、アミノ基、ヒドロキシ基、アルコキシ基、シクロアルコキシ基、ハロアルキル基、シアノ基、チオアルキル基、スルフォ基、スルホン基、スルホキシド基、アリール基またはヘテロアリール基から選択され、前記アルキル基、シクロアルキル基、ヘテロシクリル基、アリール基またはヘテロアリール基は、それぞれ独立にヒドロキシ基、ハロゲン、アルキル基、アルコキシ基、シクロアルキル基、ヘテロシクリル基、アリール基およびヘテロアリール基から選択される1つまたは複数の置換基で置換される。
1.細胞培養:Hep3B2.1-7-Luc細胞はインビトロで付着培養し、培養条件は、EMEM培地に1.5g/L重炭酸ナトリウム、10%熱不活化ウシ胎児血清、100U/mlペニシリンおよび100μg/mlストレプトマイシンを加えて、37℃、5%CO2で培養した。週2回の継代処理を行った。細胞が指数増殖期にあるとき、細胞を収集し、カウントし、接種した。
1)適切な量のD-ルシフェリン(luciferin)を秤量し、DPBSで15mg/mlの濃度を調製し、0.2umフィルターで濾過および滅菌し、-20℃の暗所で保存した。
Claims (7)
- 下記式のいずれかで示される化合物、またはその互変異性体、メソ体、ラセミ体、エナンチオマー、ジアステレオマー、またはその混合物形態、またはその薬学的に許容される塩。
- 治療有効量の請求項1に記載の化合物またはその互変異性体、メソ体、ラセミ体、エナンチオマー、ジアステレオマー、またはその混合物形態、またはその薬学的に許容される塩、ならびに1つもしくは複数の薬学的に許容される担体、希釈剤または賦形剤を含む医薬組成物。
- がんを予防および/または治療するための薬物の調製における、請求項1に記載の化合物またはその互変異性体、メソ体、ラセミ体、エナンチオマー、ジアステレオマー、またはその混合物形態、またはその薬学的に許容される塩、または請求項2に記載の医薬組成物の使用。
- 前記がんは、乳がん、子宮頸がん、結腸がん、肺がん、胃がん、直腸がん、膵臓がん、脳がん、皮膚がん、口腔がん、前立腺がん、骨がん、腎臓がん、卵巣がん、膀胱がん、肝がん、卵管腫瘍、卵巣腫瘍、腹膜腫瘍、IV期黒色腫、神経膠腫、神経膠芽腫、肝細胞がん、乳様突起腎腫瘍、頭頸部腫瘍、白血病、リンパ腫、骨髄腫、非小細胞肺がん、頭頸部がん、子宮がん、精巣がん、卵管がん、子宮内膜がん、膣がん、外陰がん、肛門がん、食道がん、小腸がん、内分泌系がん、甲状腺がん、副甲状腺がん、副腎がん、尿道がん、陰茎がん、移行上皮がん、尿管がん、腎細胞がん、腎盂がん、ホジキン病、非ホジキンリンパ腫、軟部肉腫、小児固形腫瘍、リンパ球性リンパ腫、中枢神経系(CNS)腫瘍、原発性中枢神経系リンパ腫、腫瘍血管新生(tumor angiogenesis)、脊髄腫瘍、脳幹神経膠腫、下垂体腺腫、黒色腫、カポジ肉腫、類表皮癌、扁平上皮癌(squamous cell carcinoma)、T細胞リンパ腫、慢性または急性白血病、および/または前記様々ながんの組み合わせを含むことを特徴とする
請求項3に記載の使用。 - がん転移を阻害するための薬物の調製における、請求項1に記載の化合物またはその互変異性体、メソ体、ラセミ体、エナンチオマー、ジアステレオマー、またはその混合物形態、またはその薬学的に許容される塩、または請求項2に記載の医薬組成物の使用。
- アシドーシス(acidosis)によって引き起こされる疾患を予防および/または治療するための薬物の調製における、請求項1に記載の化合物またはその互変異性体、メソ体、ラセミ体、エナンチオマー、ジアステレオマー、またはその混合物形態、またはその薬学的に許容される塩、または請求項2に記載の医薬組成物の使用。
- がんの治療またはがん転移を阻害するための薬物の調製における、請求項1に記載の化合物またはその互変異性体、メソ体、ラセミ体、エナンチオマー、ジアステレオマー、またはその混合物形態、またはその薬学的に許容される塩の、少なくとも1つの他の抗癌剤との組み合わせによる使用。
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Title |
---|
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