JP2021501208A - 急性骨髄性白血病又は転移性乳癌の予防又は治療用薬剤学的組成物 - Google Patents
急性骨髄性白血病又は転移性乳癌の予防又は治療用薬剤学的組成物 Download PDFInfo
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- JP2021501208A JP2021501208A JP2020543443A JP2020543443A JP2021501208A JP 2021501208 A JP2021501208 A JP 2021501208A JP 2020543443 A JP2020543443 A JP 2020543443A JP 2020543443 A JP2020543443 A JP 2020543443A JP 2021501208 A JP2021501208 A JP 2021501208A
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- 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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
-
- 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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
-
- 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
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/32—Oxygen atoms
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- C07D209/04—Indoles; Hydrogenated indoles
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Abstract
Description
MV4;11個のヒト急性骨髄性白血病細胞をAmerican Type Culture Collection(ATCC, Rockville, MD, USA, CRL-9591)から購入し、10%ウシ胎児血清、1%ペニシリン/ストレプトマイシン及び4mML−グルタミン(Life Technology, Grand Island, NY)を補充したIMDM培地(Sigma Co., St. Louis, MO, USA)で細胞を培養した。MDA−MB−231(転移性乳癌,ATCC HTB−26)、Jurkat(ヒト急性Tリンパ性白血病,ATCC TIB−152)及びK−562(ヒト慢性骨髄性白血病,ATCC CCL−243)細胞はRPMI−1640(シグマ社)で培養し、MCF7(ヒト乳房腺癌,ATCC HTB−22)及びPC−3(ヒト前立腺腺癌,ATCC CRL−1435)細胞は10%ウシ胎児血清、1%ペニシリン/ストレプトマイシンを補充したDMEM(シグマ社)培地で培養した。培養した細胞を3℃、5%CO2で培養した。
化合物1〜化合物47をデザインして合成した。
以下、合成模式図3により得られるindirubin−3’−oxime誘導体のalkyl aminationによる代表的な合成法を示す。
以下、合成模式図3により得られるindirubin−3’−oxime誘導体のalkylationによる代表的な合成法を示す。
以下、合成模式図3により得られるindirubin−3’−oxime carboxylic acid誘導体の代表的な合成法を示す。
生成物11d:Methyl (2Z,3E)-3-(hydroxyimino)-2'-oxo-[2,3'-biindolinylidene]-5'-carboxylate(化合物1)
1H NMR (400 MHz, DMSO-d6) δ ppm11.76 - 11.80 (m, 1 H), 11.05 - 11.10 (m, 1 H), 9.17 - 9.21 (m, 1 H), 8.24 (d, J=8.01Hz, 1H), 7.73 - 7.78 (m, 1H), 7.36 - 7.42 (m, 2H), 7.00 - 7.06 (m, 1H), 6.92 - 6.98 (m, 1H), 3.79 - 3.86 (m, 3H).
生成物18d:Methyl (2Z,3E)-3-((2-bromoethoxy)imino)-2'-oxo-[2,3'-biindolinylidene]-5'-carboxylate(化合物2)
1H NMR (400 MHz, DMSO-d6) δ ppm 11.68(s, 1H), 11.18(s, 1H), 9.36(d, J=1.6 Hz, 1H), 8.23 (d, J=7.6 Hz, 1H), 7.83 (dd, J=8.0, 1.6 Hz, 1H), 7.48(m, 2H), 7.10(m, 1H), 7.01(d, J=8.0 Hz, 1H), 4.98(t, J=5.6 Hz, 2H), 4.06(t, J=5.6 Hz, 2H), 3.86 (s, 3H).
生成物16b:Methyl (2Z,3E)-3-((2-aminoethoxy)imino)-2'-oxo-[2,3'-biindolinylidene]-5'-carboxylate hydrochloride(化合物3)
1H NMR (400 MHz, DMSO-d6) δ ppm11.66 (s, 1H),11.18 (s, 1H), 9.30 (d, J=1.60 Hz, 1H), 8.24 (d, J=7.78 Hz, 1H), 8.17 (brs, 2H), 7.80 (dd, J=8.13, 1.72 Hz, 1H), 7.41 - 7.48 (m, 2H), 7.04 (ddd, J=7.90, 5.72,2.63 Hz, 1H), 6.98 (d, J=8.01 Hz, 1H), 4.78 - 4.85 (m, 2H), 3.79 - 3.86 (m, 3H), 3.47 (d, J=4.81 Hz, 2H).
生成物24as:Methyl (2Z,3E)-2'-oxo-3-((2-(piperazin-1-yl)ethoxy)imino)-[2,3'-biindolinylidene]-5'-carboxylate dihydrochloride(化合物4,LDD−1937)
1H NMR (400 MHz, DMSO-d6) δ ppm11.70(s, 1H), 11.23(s, 1H), 9.36(s, 1H), 8.27(d, J=7.6 Hz, 1H), 7.84(d, J=8.4 Hz, 1H), 7.48(m, 2H), 7.07(m, 1H), 7.02(d, J=8.8 Hz, 1H), 5.03(m, 2H), 3.88(s, 3H), 3.30 (m, 10H, overlapped with DMSO).
生成物24bs:Methyl (2Z,3E)-3-((2-(4-methylpiperazin-1-yl)ethoxy)imino)-2'-oxo-[2,3'-biindolinylidene]-5'-carboxylate dihydrochloride(化合物5)
1H NMR (400 MHz, DMSO-d6) δ ppm11.71(s, 1H), 11.22(s, 1H), 9.38(d, J=1.6 Hz, 1H), 8.24(d, J=7.6 Hz, 1H), 7.84(dd, J=8.4, 1.6 Hz, 1H), 7.48(m, 2H), 7.08(m, 1H), 7.02(d, J=8.4 Hz, 1H), 4.96(m, 2H), 3.87(s, 3H), 3.30(m, 10H, overlapped with water).
生成物24cs:Methyl (2Z,3E)-3-((2-morpholinoethoxy)imino)-2'-oxo-[2,3'-biindolinylidene]-5'-carboxylate hydrochloride(化合物6)
1H NMR (400 MHz, DMSO-d6) δ11.70(s, 1H), 11.22(s, 1H), 10.94(brs, 1H, morpholine N+-H), 9.36(s, 1H), 8.26(d, J=7.6 Hz, 1H), 7.84(dd, J=8.0, 2.0 Hz, 1H), 7.49(m, 2H), 7.09(m, 1H), 7.02(d, J=8.0 Hz, 1H), 5.08(brs, 2H), 3.97(m, 2H), 3.80(s, 3H), 3.81(m, 4H), 3.56(m, 2H), 3.18(m, 2H, partially overlapped with water).
生成物32:(2Z,3E)-3-(hydroxyimino)-2'-oxo-[2,3'-biindolinylidene]-5'-carboxylic acid(化合物7)
1H NMR (400 MHz, DMSO-d6) δ ppm 11.68(s, 1H), 11.23(s, 1H), 8.73 - 8.78 (m, 1H), 8.18 (s, 1H), 8.01(d, J=5.04 Hz, 1H), 7.49 (m, 2H),6.95(d, J=8.0 Hz, 1H).
生成物35:(2Z,3E)-3-((2-bromoethoxy)imino)-2'-oxo-[2,3'-biindolinylidene]-5'-carboxylic acid(化合物8)
1H NMR (400 MHz, DMSO-d6) δ ppm 11.66(s, 1H), 11.11(s, 1H), 9.34(s, 1H), 8.22(d, J=7.6 Hz, 1H), 7.80(d, J=8.0 Hz, 1H), 7.63(m, 2H), 7.08(m, 1H), 6.97(d, J=8.4 Hz, 1H), 4.96(t, J=5.6 Hz, 2H), 4.03(t, J=5.6 Hz, 2H).
生成物34:(2Z,3E)-3-((2-aminoethoxy)imino)-2'-oxo-[2,3'-biindolinylidene]-5'-carboxylic acid hydrochloride(化合物9)
1H NMR (400 MHz, DMSO-d6) δ ppm 11.68(s, 1H), 11.18(s, 1H), 9.35(d, J=1.2 Hz, 1H), 8.26(d, J=7.6 Hz, 1H), 8.17(s, 3H, H+), 7.82(dd,J=8.0, 1.6 Hz, 1H), 7.48(m, 2H), 7.08(m, 1H), 7.00(d, J=8.4 Hz, 1H), 4.83(t, J=5.2 Hz, 2H), 3.45 (t, J=5.2 Hz, 2H).
生成物36as:(2Z,3E)-2'-oxo-3-((2-(piperazin-1-yl)ethoxy)imino)-[2,3'-biindolinylidene]-5'-carboxylic acid dihydrochloride(化合物10,LDD−1940)
1H NMR (400 MHz, DMSO-d6) δ ppm 11.69(s, 1H), 11.17(s, 1H), 9.37(s, 1H), 8.91(brs, 2H, piperazine N+-H), 8.23(d, J=7.6 Hz, 1H), 7.82(d, J=8.4 Hz, 1H), 7.47(m, 2H), 7.07(m, 1H), 7.00(d, J=8.4 Hz, 1H), 4.92(brs, 2H), 3.05(m, 10H, overlapped with water).
生成物36bs:(2Z,3E)-3-((2-(4-methylpiperazin-1-yl)ethoxy)imino)-2'-oxo-[2,3'-biindolinylidene]-5'-carboxylic acid dihydrochloride(化合物11)
1H NMR (400 MHz, DMSO-d6) δ ppm 11.68(s, 1H), 11.16(s, 1H), 9.36(s, 1H), 8.23(d, J=8.0 Hz, 1H), 7.82(d, J=8.0 Hz, 1H), 7.47(m, 2H), 7.07(m, 1H), 6.99(d, J=8.0 Hz, 1H), 4.93(brs, 2H), 3.17(m, 10H, overlapped with water), 2.77 (s, 3H).
生成物36cs:(2Z,3E)-3-((2-morpholinoethoxy)imino)-2'-oxo-[2,3'-biindolinylidene]-5'-carboxylic acid hydrochloride(化合物12)
1H NMR (400 MHz, DMSO-d6) δ ppm 11.67(s, 1H), 11.27(brs, 1H, morpholine N+-H), 11.18(s, 1H), 9.34(s, 1H), 8.25(d, J=7.6 Hz, 1H), 7.82(d, J=8.4 Hz, 1H), 7.48(m, 2H), 7.08(m, 1H), 6.99(d, J=8.0 Hz, 1H), 5.06(brs, 2H), 3.96(m, 2H), 3.80(m, 4H), 3.53(m, 2H), 3.24(m, 2H, partially overlapped with water).
生成物10a:(2Z,3E)-5-hydroxy-3-(hydroxyimino)-5'-nitro-[2,3'-biindolinylidene]-2'-one(化合物13)
1H NMR(300MHz, DMSO-d6)δ (ppm); 13.87(1H, s, NOH), 11.78(1H, s, NH), 11.35(1H, s, N-H), 9.41(1H, d, J=2.8 Hz), 9.32(1H, s, O-H), 8.05(1H, dd, J=11.6, 2.8 Hz), 7.76(1H, d, J=3.2 Hz), 7.29(1H, d, J=11.6 Hz), 7.04(1H, d, J=11.2 Hz) 6.86(1H, dd, J=11.2, 3.2 Hz)
生成物20bs:(2Z,3E)-5-hydroxy-3-((2-(4-methylpiperazin-1-yl)ethoxy)imino)-5'-nitro-[2,3'-biindolinylidene]-2'-one dihydrochloirde(化合物14)
1H NMR (400 MHz, DMSO-d6) δ (ppm); 11.66(s, 1H), 11.46(s, 1H), 9.56(d, J=2.4 Hz, 1H), 9.51(brs, 1H), 8.10(dd, J=8.8, 2.4 Hz, 1H), 7.75(s, 1H), 7.32(d, J=8.8 Hz, 1H), 7.08(d, J=8.8 Hz, 1H) 6.93(dd, J = 8.8, 2.4 Hz, 1H), 5.01(brs, 2H), 3.27(m, 10H, partially overlapped with water), 2.8(s, 3H).
生成物16a:(2Z,3E)-3-((2-aminoethoxy)imino)-5'-nitro-[2,3'-biindolinylidene]-2'-one hydrochloirde(化合物15)
1H NMR (400 MHz, DMSO-d6) d ppm
11.66 (s, 1 H) 11.18 (s, 1 H) 9.30 (d, J=1.60 Hz, 1 H) 8.24 (d, J=7.78 Hz, 1 H) 8.17 (br. s., 2 H) 7.80 (dd, J=8.13, 1.72 Hz, 1 H) 7.41 - 7.48 (m, 2 H) 7.04 (ddd, J=7.90, 5.72, 2.63 Hz, 1 H) 6.98 (d, J=8.01 Hz, 1 H) 4.78 - 4.85 (m, 2 H) 3.79 - 3.86 (m, 3 H) 3.47 (d, J=4.81 Hz, 2 H)
生成物21as:(2Z,3E)-5'-nitro-3-((2-(piperazin-1-yl)ethoxy)imino)-[2,3'-biindolinylidene]-2'-one dihydrochloride(化合物16)
1H NMR(400MHz, DMSO-d6) δ (ppm); 11.70(s, 1H), 11.25(s, 1H), 9.45 (d, J=2.4 Hz, 1H), 8.23 (d, J=8.4 Hz, 2H), 8.03 (m, 1H), 7.50 (d, J=2.4 Hz, 1H), 7.43 (m, 1H), 7.04 (m, 2H), 4.82 (m, 2 H) 3.81 (m, 3 H) 3.42 (m, 2 H)
生成物15as:(2Z,3E)-5-fluoro-5'-nitro-3-((2-(piperazin-1-yl)ethoxy)imino)-[2,3'-biindolinylidene]-2'-one(化合物17)
1H NMR(400MHz, DMSO-d6) δ (ppm); 11.66(s, 1H), 11.47(s, 1H), 9.51(d, J=2.4 Hz, 1H), 9.48(s, 1H), 8.24(brs, 3H), 8.09(dd, J=8.4, 2.4 Hz, 1H), 7.78(d, J=2.4 Hz, 1H), 7.30 (d, J=8.4 Hz, 1H), 7.07 (d, J=8.8 Hz, 1H), 6.95 (dd, J=8.4, 2.4 Hz, 1H), 4.87 (t, J=4.4 Hz, 2H), 3.49 (t, J=4.4 Hz, 2H).
生成物25bs:(2Z,3E)-5-fluoro-3-((2-(4-methylpiperazin-1-yl)ethoxy)imino)-5'-nitro-[2,3'-biindolinylidene]-2'-one dihydrochloride(化合物18)
1H NMR (400 MHz, DMSO-d6) δ (ppm); 9.58(1H, d, J=2.1 Hz), 8.14(1H, m), 7.97(1H, dd, J=8.9 ,2.4 Hz), 7.57(1H, m), 7.41(1H, m), 7.08(1H, m), 4.87(2H, m), 2.96(2H, m), 2.38(4H, m), 2.15(3H, m).
生成物25ds:(2Z,3E)-5-fluoro-5'-nitro-3-((2-(piperidin-1-yl)ethoxy)imino)-[2,3'-biindolinylidene]-2'-one hydrochloride(化合物19)
1H NMR (400 MHz, DMSO-d6) δ (ppm); 11.80(m, 1H), 10.79(s, 1H), 8.46(dd, J=11.3, 2.4 Hz, 1H), 8.19(m, 1H), 7.48(m, 2H), 7.08(m, 1H), 7.01(m, 1H), 6.90(m, 1H), 4.69(t, J=6.1 Hz, 2H), 2.90(m, 2 H), 2.24(s, 2 H), 1.94(m, 1 H), 1.58(m, 3 H), 1.40(m, 2 H)
生成物25cs:(2Z,3E)-5-fluoro-5'-nitro-3-((2-(pyrrolidin-1-yl)ethoxy)imino)-[2,3'-biindolinylidene]-2'-one hydrochloride(化合物20)
1H NMR (400 MHz, DMSO-d6) δ (ppm); 9.56(s, 1H), 8.07 d, J= 8.8 Hz, 1H), 7.88(d, J=8.8 Hz, 1H), 7.48(s, 1H), 7.34(s, 1H), 7.03(d, J=9.6 Hz, 1H), 4.84(m, 2H), 4.12(m, 2H).
生成物26as:(2Z,3E)-5,5'-difluoro-3-((2-(piperazin-1-yl)ethoxy)imino)-[2,3'-biindolinylidene]-2'-one dihydrochloride(化合物21)
1H NMR (400 MHz, DMSO-d6) δ (ppm); 11.80(m, 1H), 10.83(m, 1H), 8.44(m, 1H), 8.01(m, 1H), 7.49(m, 1H), 7.38(m, 1H), 7.01(m, 1H), 6.87(dd, J=4.9 Hz, 1H), 4.75(m, 2H), 2.90(m, 2H), 2.74(m, 3H), 2.47(m, 3H).
生成物26bs:(2Z,3E)-5,5'-difluoro-3-((2-(4-methylpiperazin-1-yl)ethoxy)imino)-[2,3'-biindolinylidene]-2'-one dihydrochloride(化合物22)
1H NMR (400 MHz, DMSO-d6) δ (ppm); 11.77(m, 1H), 10.81(m, 1H), 8.44(m, 1H), 7.99(dd, J=8.9, 2.8 Hz, 1H), 7.47(dd, J=8.9, 4.6 Hz, 1H), 7.34(td, J=9.0, 2.8 Hz, 1H), 6.98(td, J=8.9, 2.8 Hz, 1H), 6.89(m, 1H), 4.74(m, 2H), 2.92(m, 2H), 2.38(m, 3H), 2.15(m, 3H).
生成物26es:(2Z,3E)-5,5'-difluoro-3-((2-(piperidin-1-yl)ethoxy)imino)-[2,3'-biindolinylidene]-2'-one hydrochloride(化合物23)
1H NMR (400 MHz, DMSO-d6) δ (ppm); 11.78(m, 1H), 10.79(brs, 1H), 8.41(dd, J=11.3, 2.8 Hz, 1H), 7.97(dd, J=8.7, 2.6 Hz, 1H), 7.47(dd, J=8.7, 4.4 Hz, 1H), 7.38(m, 1H), 7.01(m, 1H), 6.89(m, 1H), 4.69(t, J=6.0 Hz, 2H), 2.85(t, J=6.1 Hz, 2H), 1.51(q, J=5.5 Hz, 4H), 1.42 (m, 2H).
生成物26ds:(2Z,3E)-5,5'-difluoro-3-((2-(pyrrolidin-1-yl)ethoxy)imino)-[2,3'-biindolinylidene]-2'-one hydrochloride(化合物24)
1H NMR (400 MHz, DMSO-d6) δ (ppm); 10.86(m, 1H), 8.41(dd, J=11.3, 2.8 Hz, 1H), 7.92(dd, J=8.6, 2.8 Hz, 1H), 7.47 (dd, J=8.9, 4.6 Hz, 1H), 7.34(td, J=9.1, 2.6 Hz, 1H), 6.97(td, J=8.8, 2.6 Hz, 1H), 6.89(m, 1H), 4.70(t, J=6.0 Hz, 1H), 3.00 (t, J=6.0 Hz, 2H), 2.60(m, 4H), 1.69 (dt, J=6.6, 3.1 Hz, 4H).
生成物26gs:(2Z,3E)-3-((2-(4-aminopiperidin-1-yl)ethoxy)imino)-5,5'-difluoro-[2,3'-biindolinylidene]-2'-one dihydrochloride(化合物25)
1H NMR (400 MHz, DMSO-d6) δ (ppm); 8.32(dd, J=11.1, 2.6 Hz, 1H), 8.01(dd, J=8.7, 2.6 Hz, 1H), 7.48(d, J=8.9, 4.6 Hz, 1H), 7.40(m, 1H), 7.04(m, 1H), 6.88(dd, J=8.6, 4.9 Hz, 1H), 5.01(m, 2H), 3.37 (m, 4H), 2.96(dd, J=11.6 Hz, 2H), 2.15 (m, 4H), 1.73 (m, 1H).
生成物26fs:(2Z,3E)-5,5'-difluoro-3-((2-(piperidin-4-ylamino)ethoxy)imino)-[2,3'-biindolinylidene]-2'-one dihydrochloride(化合物26)
1H NMR (400 MHz, DMSO-d6) δ (ppm); 8.41(dd, J=11.3, 2.8 Hz, 1H), 7.96(dd, J=8.7, 2.6 Hz, 1H), 7.47(dd, J=8.9, 4.3 Hz, 1H), 7.38(1H, m), 6.97(dd, J=9.2, 2.8 Hz, 1H), 6.86(dd, J=8.6, 4.9 Hz, 1H), 4.69(t, J=6.0 Hz, 2H), 2.93(m, 4H), 2.15(m, 2H), 1.72(m, 2H), 1.33(m, 2H).
生成物26cs:(2Z,3E)-5,5'-difluoro-3-((2-morpholinoethoxy)imino)-[2,3'-biindolinylidene]-2'-one hydrochloride(化合物27)
1H NMR (400 MHz, DMSO-d6) δ (ppm); 9.59(d, J=2.4 Hz, 1H), 8.13(m, 1H), 7.97(d, J=6.1 Hz, 1H), 7.51(s, 1H), 7.37(s, 1H), 7.07(d, J=8.6 Hz, 1H), 4.83(t, J=5.8 Hz, 1H), 3.17(s, 2H), 2.94(m, 4H), 1.53(m, 5H), 1.38(dd, J=5.3, 0.8 Hz, 3H).
生成物23as:(2Z,3E)-3-((2-(piperazin-1-yl)ethoxy)imino)-[2,3'-biindolinylidene]-2'-one dihydrochloride(化合物28)
1H NMR (400 MHz, DMSO-d6) δ (ppm); 11.84(1H, m, N-H), 10.78(1H, s, N-H), 8.62(1H,d, J=7.9 Hz), 8.17(1H, d, J=7.6 Hz), 7.46(2H, m), 7.15(1H ,td, J=7.6, 1.2 Hz), 7.03(1H, m), 6.99(1H, m), 6.90(1H, d, J=7.6 Hz), 4.69(2H, t, J=6.0 Hz), 3.46(4H, m), 2.84(2H, t, J=6.1 Hz), 2.69(2H, t, J=4.7 Hz), 2.45(2H, m).
生成物23bs:(2Z,3E)-3-((2-(4-methylpiperazin-1-yl)ethoxy)imino)-[2,3'-biindolinylidene]-2'-one dihydrochloride(化合物29)
1H NMR (400 MHz, DMSO-d6) δ (ppm); 11.70(1H, m, N-H), 10.78(1H, s), 8.64(1H, m), 8.17(1H, d, J=7.9 Hz), 7.42(1H, d, J=1.2 Hz), 7.16(1H, td, J=7.6, 1.2 Hz), 7.06(1H, m), 7.00(1H, m), 6.93(1H, m), 4.69(2H, t, J=6.1 Hz), 2.96(2H, m), 2.54(4H, m), 2.39(4H,m), 2.14(3H, s).
生成物23ds:(2Z,3E)-3-((2-(piperidin-1-yl)ethoxy)imino)-[2,3'-biindolinylidene]-2'-one hydrochloride(化合物30)
1H NMR (400 MHz, DMSO-d6) δ (ppm); 8.61(1H, d, J=6.0 Hz), 8.16(1H, d, J=6.0 Hz), 7.43(1H, m), 7.15(1H, m), 7.03(1H, s), 6.97(1H, m), 6.89(1H, d, J=6.0 Hz), 4.69(2H, m), 2.86(2H, m), 2.08(4H, s), 1.52(3H, m), 1.43(2H, m).
生成物23cs:(2Z,3E)-3-((2-(pyrrolidin-1-yl)ethoxy)imino)-[2,3'-biindolinylidene]-2'-one hydrochloride(化合物31)
1H NMR (400 MHz, DMSO-d6) δ (ppm); 11.69(1H, s, br), 10.76(1H, s), 8.66(1H, m), 8.18(1H, m), 7.46(2H, m), 7.18(1H, m), 7.06(1H, m), 6.98(1H, td, J=7.7, 1.1 Hz), 6.91(1H, dd, J=7.7, 0.6 Hz), 4.69(2H, t, J=6.0 Hz), 2.99(2H, t, J=6.0 Hz), 2.59(4H, m), 1.69(4H, dt, J=6.9, 3.2 Hz).
生成物23es:(2Z,3E)-3-((2-(piperidin-4-ylamino)ethoxy)imino)-[2,3'-biindolinylidene]-2'-one dihydrochloride(化合物32)
1H NMR (400 MHz, DMSO-d6) δ (ppm); 8.62(1H, d, J=7.6 Hz), 8.17(1H, d, J=7.7 Hz), 7.46(2H,m), 7.15(1H, td, J=7.56, 1.2 Hz), 7.03(1H, td, J=7.2, 1.6 Hz), 7.01(1H, m), 6.91(1H, d, J=7.7 Hz), 4.68(2H, t, J=6.1 Hz), 2.92(4H, m), 2.17(2H, m).
生成物22as:(2Z,3E)-5'-fluoro-3-((2-(piperazin-1-yl)ethoxy)imino)-[2,3'-biindolinylidene]-2'-one dihydrochloride(化合物33)
1H NMR (400 MHz, DMSO-d6) δ (ppm); 11.83(1H, m, N-H), 10.84(1H, m, N-H), 8.45(1H, dd, J=11.3, 2.8 Hz), 8.21(1H, m), 7.47(2H, m), 7.09(1H, m), 6.99(1H, m), 6.87(1H, dd, J=8.4, 5.0 Hz), 4.76(3H, m), 2.91(2H, m), 2.70(4H, m), 2.47(3H, m).
生成物22bs:(2Z,3E)-5'-fluoro-3-((2-(4-methylpiperazin-1-yl)ethoxy)imino)-[2,3'-biindolinylidene]-2'-one dihydrochloride(化合物34)
1H NMR (400 MHz, DMSO-d6) δ (ppm); 11.84(1H, m, N-H), 10.81(1H, m, N-H), 8.47(1H, dd, J=11.3, 2.7 Hz), 8.20(1H, m), 7.46(2H, m), 7.13 (1H,m), 6.99(1H, m), 6.85(1H, dd, J=8.4, 5.0 Hz), 4.74(3H, m), 2.90(2H, m), 2.72(4H, m), 2.45(3H, m), 2.14(3H, m).
生成物22ds:(2Z,3E)-5'-fluoro-3-((2-(piperidin-1-yl)ethoxy)imino)-[2,3'-biindolinylidene]-2'-one hydrochloride(化合物35)
1H NMR (400 MHz, DMSO-d6) δ (ppm); 11.80(m, 1H), 10.79(s, 1H), 8.46 (dd, J=11.3, 2.4 Hz, 1H), 8.19(m, 1H), 7.48(m, 2H), 7.08(m, 1H), 7.01(m, 1H), 6.90(m, 1H), 4.69(t, J=6.1 Hz, 2H), 2.90(m, 2H), 2.24(s, 2H), 1.94(m, 1H), 1.58(m, 3H), 1.40(m, 2H).
生成物22cs:(2Z,3E)-5'-fluoro-3-((2-(pyrrolidin-1-yl)ethoxy)imino)-[2,3'-biindolinylidene]-2'-one hydrochloride(化合物36)
1H NMR (400 MHz, DMSO-d6) δ (ppm); 10.78(1H, s, br), 8.46(1H, dd, J=11.1, 2.6 Hz), 8.18(1H, m), 7.47(2H, m), 7.09(1H, m), 6.96(1H, dd, J=9.0, 2.6 Hz), 6.87(1H, dd, J=8.4, 5.0 Hz), 4.69(2H, t, J=6.1 Hz), 3.01(2H, t, J=6.0 Hz), 2.61(4H, m), 1.68(4H, dt, J=7.0, 3.2 Hz).
生成物22es:(2Z,3E)-5'-fluoro-3-((2-(piperidin-4-ylamino)ethoxy)imino)-[2,3'-biindolinylidene]-2'-one dihydrochloride(化合物37)
1H NMR (400 MHz, DMSO-d6) δ (ppm); 8.48(1H, m), 8.17(1H, dd, J=7.6, 0.9 Hz), 7.46 (2H, m), 6.98(1H, d, J=2.8 Hz), 6.89(1H, m), 4.68(2H, t, J=6.1 Hz), 2.93 (4H, m), 2.15(2H, m).
生成物27a:(2Z,3E)-5'-chloro-3-((2-(piperazin-1-yl)ethoxy)imino)-[2,3'-biindolinylidene]-2'-one dihydrochloride(化合物38)
1H NMR (400MHz, DMSO-d6)δ(ppm) 11.83 (s, 1H), 10.84 (s, 1H), 8.60 (s, 1H), 8.24 (d,J=7.6Hz, 1H), 7.45 (m, 2H), 7.14 (m, 2H), 6.88 (d,J=7.9Hz, 1H), 4.69(t, J=6.0 Hz, 2H), 3.46(m, 4H), 2.84(t, J=6.1 Hz, 2H), 2.69(t, J=4.7Hz, 2H), 2.45(m, 2H).
生成物27b:(2Z,3E)-5'-chloro-3-((2-(4-methylpiperazin-1-yl)ethoxy)imino)-[2,3'-biindolinylidene]-2'-one dihydrochloride(化合物39)
1H NMR (400MHz, DMSO-d6)δ(ppm) 11.85 (s, 1H), 10.82 (s, 1H), 8.59 (s, 1H), 8.19 (d,J=7.6Hz, 1H), 7.65 (m, 2H), 7.14 (m, 2H), 6.90 (d,J=7.9Hz, 1H), 4.74(m, 2H), 2.91(m, 2H), 2.40(m, 3H), 2.15(m, 3H).
生成物28a:(2Z,3E)-5'-bromo-3-((2-(piperazin-1-yl)ethoxy)imino)-[2,3'-biindolinylidene]-2'-one dihydrochloride(化合物40)
1H NMR (400MHz, DMSO-d6)δ(ppm) 11.82 (s, 1H) , 10.76 (s, 1H), 8.65 (s, 1H), 8.19 (d, J = 8.0 Hz, 1H), 7.45 (m, 2H), 7.28 (d, J=8.2Hz, 1H), 7.08 (m, 1H), 6.88 (d, J = 8.0 Hz, 1H) 4.72(m, 3H), 2.87(m, 2H), 2.70(4H, m), 2.47(3H, m).
生成物28b:(2Z,3E)-5'-bromo-3-((2-(4-methylpiperazin-1-yl)ethoxy)imino)-[2,3'-biindolinylidene]-2'-one dihydrochloride(化合物41)
1H NMR (400MHz, DMSO-d6)δ(ppm) 11.82 (s, 1H) , 10.77 (s, 1H), 8.65 (s, 1H), 8.19 (d, J = 8.0 Hz, 1H), 7.45 (m, 2H), 7.28 (d, J=8.2Hz, 1H), 7.08 (m, 1H), 6.88 (d, J = 8.0 Hz, 1H), 4.74(m, 3H), 2.93(m, 2H), 2.75(m, 4H), 2.45(m, 3H), 2.17(m, 3H,).
生成物29a:(2Z,3E)-5'-iodo-3-((2-(piperazin-1-yl)ethoxy)imino)-[2,3'-biindolinylidene]-2'-one dihydrochloride(化合物42)
1H NMR (400MHz, DMSO-d6)δ(ppm) 11.83 (s, 1H), 10.80 (s, 1H), 8.85 (s, 1H), 8.20 (d, J = 8.0 Hz, 1H), 7.45 (m, 3H), 7.06 (m, 1H), 6.75 (d, J = 8.0 Hz, 1H) 4.75(m, 3H), 2.85(m, 2H), 2.71(4H, m), 2.45(3H, m).
生成物29b:(2Z,3E)-5'-iodo-3-((2-(4-methylpiperazin-1-yl)ethoxy)imino)-[2,3'-biindolinylidene]-2'-one dihydrochloride(化合物43)
1H NMR (400MHz, DMSO-d6)δ(ppm) 11.82 (s, 1H) , 10.77 (s, 1H), 8.66 (s, 1H), 8.21 (d, J = 8.0 Hz, 1H), 7.46 (m, 3H), 7.08 (m, 1H), 6.74 (d, J = 8.0 Hz, 1H), 4.75(m, 3H), 2.90(m, 2H), 2.72(m, 4H), 2.42(m, 3H), 2.17(m, 3H,).
生成物30a:(2Z,3E)-3-((2-(piperazin-1-yl)ethoxy)imino)-5'-(trifluoromethoxy)-[2,3'-biindolinylidene]-2'-one dihydrochloride(化合物44)
1H NMR (400MHz, DMSO-d6)δ(ppm) 11. 73 (s, 1H), 10.79 (s, 1H), 8.57 (s, 1H), 8.27 (d, J = 7.5 Hz, 1H), 7.41 (m, 2H), 6.99 (m, 2H), 6.94 (d, J = 8.4 Hz, 1H) 4.73(m, 2H), 2.87(m, 2H), 2.76(m, 3H), 2.45(m, 3H).
生成物30b:(2Z,3E)-3-((2-(4-methylpiperazin-1-yl)ethoxy)imino)-5'-(trifluoromethoxy)-[2,3'-biindolinylidene]-2'-one dihydrochloride(化合物45)
1H NMR (400MHz, DMSO-d6)δ(ppm) 11.68 (s, 1H) 10.88 (s, 1H), 8.60 (s, 1H), 8.24 (1H, d, J = 7.5 Hz), 7.40 (2H, m), 7.01 (2H, m), 6.94 (1H, d, J = 8.4 Hz) 4.82(2H, m), 2.98(2H, m), 2.41(4H, m), 2.18(3H, m).
生成物31a:(2Z,3E)-5'-methoxy-3-((2-(piperazin-1-yl)ethoxy)imino)-[2,3'-biindolinylidene]-2'-one dihydrochloride(化合物46)
1H NMR (400MHz, DMSO-d6)δ(ppm) 11.74 (s, 1H), 10.49 (s, 1H), 8.35 (d,J= 2.2 Hz, 1H), 8.22 (d,J= 7.4 Hz, 1H), 7.40 (m, 2H), 7.02 (m, 1H), 6.75 (d,J= 8.3 Hz, 1H), 6.70 (dd,J= 7.6 Hz, 2.4 Hz, , 1H), 4.75(m, 2H), 3.72 (s, 3H), 2.90(m, 2H), 2.74(m, 3H), 2.47(m, 3H).
生成物31b:(2Z,3E)-5'-methoxy-3-((2-(4-methylpiperazin-1-yl)ethoxy)imino)-[2,3'-biindolinylidene]-2'-one dihydrochloride(化合物47)
1H NMR (400MHz, DMSO-d6)δ(ppm) 11.76 (s, 1H), 10.51 (s, 1H), 8.38 (d,J= 2.1 Hz, 1H), 8.23 (d,J= 7.4 Hz, 1H), 7.42 (m, 2H), 7.02 (m, 1H), 6.75 (d,J= 8.3 Hz, 1H), 6.72 (m,1H), 4.75(m, 2H) , 3.72 (s, 3H), 2.94(m, 2H), 2.36(m, 3H), 2.17(m, 3H).
FLT3キナーゼ活性の阻害は、HTRF(homogeneous, time-resolved fluorescence)分析を用いて測定した。FLT3キナーゼドメインを含有する組換えタンパク質は、Carna biosciences(Japan)から購入した。最適な酵素、ATP及び基質濃度は、メーカーの指示に従ってHTRF KinEASEキット(Cisbio, France)により確立した。FLT3酵素をキナーゼ反応バッファ(50mM HEPES(pH7.0),500μM ATP,0.1mMオルトバナジン酸ナトリウム,5mM MgCl2,1mM DTT,0.01%ウシ血清アルブミン(BSA),0.02%NaN3)中で、希釈した化合物及びペプチド基質と順次混合した。検出用試薬を添加し、その後Victor multilabel reader(Perkin Elmer, Waltham, MA, USA)でTR−FRET信号を測定した。IC50は、Prism version 5.01(GraphPad)を用いて非線形回帰分析(nonlinear regression)により計算した。JAK2、JAK3、cMET及びRET in vitroキナーゼ分析も、HTRF分析を用いて行った。
MV4;11細胞を雌BALB/c nu/nu(無胸腺ヌード)マウス(マウス1匹当たり5×106細胞)の側腹部に皮下接種した。腫瘍の平均体積が100mm3に達したら(概して接種後14日目)、マウスをランダムに3群に分け(対照群1群当たりn=10,5mg/kg,10mg/kg 1群当たりn=6)、PBS中5mg/kg又は10mg/kgのLDD−1937を20ml/kgで、又は純PBS(対照群)を尾静脈内に注入した。薬物又は対照群のPBSを21日間にわたって毎日注入した。腫瘍の大きさを21日間に週2回測定し、腫瘍の体積を次の式で計算した。
Balb/c nu/nu mice(Female)6−weeks−oldを中央実験動物から購入して用いた。MDA−MB−231細胞株をATCCから購入して用いた。Tumor bearing mice modelを作製するために、1匹当たりのInoculationした細胞の数を1×107個とし、溶媒としてcorning matrigel/PBS mix solution 100uLを用いた。薬物の投与は、tumor volumeの大きさが200〜300mm3になったときに開始した(Tumor volumeの測定は毎日行うことを原則とし、volumeは次の式で計算した)。
1.FLT3キナーゼ活性の阻害剤としてのLDD−1937
表1はFLT3及びMV4;11に対する阻害活性を示す表である。
MV4;11細胞は、受容体チロシンキナーゼFLT3突然変異を有する白血病細胞である。FLT3活性の構成的活性化(constitutive activation)を誘発する膜近傍ドメイン(juxtamembrane domain)において、ITD(internal tandem duplication)を有するFLT3突然変異(FLT3−ITD)がMV4;11細胞に存在する[3]。MV4;11細胞の成長と生存はFLT3活性に依存することが知られている[23]。LDD−1937による細胞毒性を測定した。それを表4に示す。不死化Tリンパ球Jurkat細胞(Immortalized T lymphocytes Jurkat cells)、前立腺癌PC−3細胞、乳癌MCF−7細胞及び赤血球減少症K562細胞も細胞毒性分析に用いた。MV4;11細胞は、他の細胞株と比較して、LDD−1937処理(GI50=1nM)に対して高い感度を示した。GI50値の観点から、LDD−1937は、MV4;11細胞に対して他の細胞株の1000〜2000倍の効能を示した。
LDD−1937のin vivo効能を試験するために、MV4;11異種移植研究を行った。MV4;11細胞をBALB/c nu/nuマウスに皮下注射し、腫瘍を約100mm3まで成長させた。次に、LDD−1937又はPBS対照群を3週間静脈内投与した。図2のAに示すように、LDD−1937群の腫瘍の大きさは、対照群の腫瘍の大きさより大幅に小さかった。特に、10mg/kg群においては、腫瘍の体積の測定3日目から腫瘍が消失した(図2のA)。腫瘍注入部位を解剖し、10mg/kg群における腫瘍の完全な消失を確認した。よって、対照群と5mg/kg群においてのみ腫瘍の重量の測定が可能であり、LDD−1937群の5mg/kgにおいて有意な減少を示した(図2のB)。投与期間中に、群間において体重に有意な差はなかった(図3)。
4種のインジルビン誘導体のin vivo効能を試験するために、MDA−MB−231異種移植研究を行った。培養した細胞をBALB/C nu/nu(female)マウスに移植し、腫瘍を約200mm3〜300mm3に成長させた。次に、4種のインジルビン誘導体LDD−2614(化合物21)、2633(化合物28)、2634(化合物34)、2635(化合物33)をそれぞれ20mg/kgで投与した。比較群としてDoxorubicin 5mg/kgを4週間投与した。図4に示すように、4種の化合物の投与後に、肝臓と腎臓の重量には大きな差がなかったが、癌組織の重量には差があった。同じ期間中に、癌組織の体積が比較群と同レベルまで減少することが確認された(図5)。腫瘍注入部位を解剖し、2633(化合物28)、2634(化合物34)、2635(化合物33)の3種の化合物が比較群と同等の抗癌効果を発揮することを確認した(図6)。
Claims (13)
- 次の化学式(1)で表される化合物、その薬学的に許容される塩、溶媒和物又は水和物。
- 前記R3は、2−ブロモエチル、化学式(2)、(3)及び(4)からなる群から選択されるいずれか1つの置換基であることを特徴とする請求項1に記載の化合物、その薬学的に許容される塩、溶媒和物又は水和物。
- 前記R3は、化学式(2)、(3)及び(4)からなる群から選択されるいずれか1つの置換基であることを特徴とする請求項1に記載の化合物、その薬学的に許容される塩、溶媒和物又は水和物。
- 前記R3は、化学式(3)又は(4)であることを特徴とする請求項1に記載の化合物、その薬学的に許容される塩、溶媒和物又は水和物。
- 前記R2はC1−C4アルキルエステルであることを特徴とする請求項1〜4のいずれか一項に記載の化合物、その薬学的に許容される塩、溶媒和物又は水和物。
- 前記C1−C4アルキルエステルはメチルエステルであることを特徴とする請求項5に記載の化合物、その薬学的に許容される塩、溶媒和物又は水和物。
- 前記R3は、化学式(2)、(3)及び(4)からなる群から選択されるいずれか1つの置換基であることを特徴とする請求項5に記載の化合物、その薬学的に許容される塩、溶媒和物又は水和物。
- 前記化学式(1)で表される化合物は、
メチル−(2Z,3E)−2'−オキソ−3−((2−(ピペラジン−1−イル)エトキシ)イミノ)−[2,3’−ビインドリニリデン]−5'−カルボキシレートジヒドロクロリド(化合物4)、
メチル−(2Z,3E)−3−(ヒドロキシイミノ)−2’−オキソ−[2,3’−ビインドリニリデン]−5’−カルボキシレート(化合物1)、
メチル−(2Z,3E)−3−((2−ブロモエトキシ)イミノ)−2’−オキソ−[2,3’−ビインドリニリデン]−5’−カルボキシレート(化合物2)、
メチル−(2Z,3E)−3−((2−アミノエトキシ)イミノ)−2’−オキソ−[2,3’−ビインドリニリデン]−5'−カルボキシレートヒドロクロリド(化合物3)、
メチル−(2Z,3E)−3−((2−(4−メチルピペラジン−1−イル)エトキシ)イミノ)−2’−オキソ−[2,3’−ビインドリニリデン]−5'−カルボキシレートジヒドロクロリド(化合物5)、
メチル−(2Z,3E)−3−((2−モルホリノエトキシ)イミノ)−2’−オキソ−[2,3’−ビインドリニリデン]−5'−カルボキシレートヒドロクロリド(化合物6)、
(2Z,3E)−3−((2−ブロモエトキシ)イミノ)−2’−オキソ−[2,3’−ビインドリニリデン]−5’−カルボン酸(化合物8)、
(2Z,3E)−3−((2−アミノエトキシ)イミノ)−2’−オキソ−[2,3’−ビインドリニリデン]−5'−カルボン酸ジヒドロクロリド(化合物9)、
(2Z,3E)−2’−オキソ−3−((2−(ピペラジン−1−イル)エトキシ)イミノ)−[2,3’−ビインドリニリデン]−5'−カルボン酸ジヒドロクロリド(化合物10)、
(2Z,3E)−3−((2−(4−メチルピペラジン−1−イル)エトキシ)イミノ)−2’−オキソ−[2,3’−ビインドリニリデン]−5'−カルボン酸ジヒドロクロリド(化合物11)、
(2Z,3E)−3−((2−モルホリノエトキシ)イミノ)−2’−オキソ−[2,3’−ビインドリニリデン]−5'−カルボキシレートヒドロクロリド(化合物12)、
(2Z,3E)−5−ヒドロキシ−3−(ヒドロキシイミノ)−5'−ニトロ−[2,3’−ビインドリニリデン]−2'−オン(化合物13)、
(2Z,3E)−5−ヒドロキシ−3−((2−(4−メチルピペラジン−1−イル)エトキシ)イミノ)−5'−ニトロ−[2,3’−ビインドリニリデン]−2'−オンジヒドロクロリド(化合物14)、
(2Z,3E)−3−((2−アミノエトキシ)イミノ)−5'−ニトロ−[2,3’−ビインドリニリデン]−2'−オンヒドロクロリド(化合物15)、
(2Z,3E)−5'−ニトロ−3−((2−(ピペラジン−1−イル)エトキシ)イミノ)−[2,3’−ビインドリニリデン]−2'−オンジヒドロクロリド(化合物16)、
(2Z,3E)−5−フルオロ−5'−ニトロ−3−((2−(ピペラジン−1−イル)エトキシ)イミノ)−[2,3’−ビインドリニリデン]−2'−オンジヒドロクロリド(化合物17)、
(2Z,3E)−5−フルオロ−3−((2−(4−メチルピペラジン−1−イル)エトキシ)イミノ)−5'−ニトロ−[2,3’−ビインドリニリデン]−2'−オンジヒドロクロリド(化合物18)、
(2Z,3E)−5−フルオロ−5'−ニトロ−3−((2−(ピペリジン−1−イル)エトキシ)イミノ)−[2,3’−ビインドリニリデン]−2'−オンヒドロクロリド(化合物19)、
(2Z,3E)−5−フルオロ−5'−ニトロ−3−((2−(ピロリジン−1−イル)エトキシ)イミノ)−[2,3’−ビインドリニリデン]−2'−オンヒドロクロリド(化合物20)、
(2Z,3E)−5,5’−ジフルオロ−3−((2−(ピペラジン−1−イル)エトキシ)イミノ)−[2,3’−ビインドリニリデン]−2’−オンジヒドロクロリド(化合物21)、
(2Z,3E)−5,5’−ジフルオロ−3−((2−(4−メチルピペラジン−1−イル)エトキシ)イミノ)−[2,3’−ビインドリニリデン]−2’−オンヒドロクロリド(化合物22)、
(2Z,3E)−5,5’−ジフルオロ−3−((2−(ピペリジン−1−イル)エトキシ)イミノ)−[2,3’−ビインドリニリデン]−2’−オンヒドロクロリド(化合物23)、
(2Z,3E)−5,5’−ジフルオロ−3−((2−(ピロリジン−1−イル)エトキシ)イミノ)−[2,3’−ビインドリニリデン]−2’−オンヒドロクロリド(化合物24)、
(2Z,3E)−3−((2−(4−アミノピペリジン−1−イル)エトキシ)イミノ)−5,5’−ジフルオロ−[2,3’−ビインドリニリデン]−2’−オンジヒドロクロリド(化合物25)、
(2Z,3E)−5,5’−ジフルオロ−3−((2−(ピペリジン−4−イルアミノ)エトキシ)イミノ)−[2,3’−ビインドリニリデン]−2’−オンジヒドロクロリド(化合物26)、
(2Z,3E)−5,5’−ジフルオロ−3−((2−モルホリノエトキシ)イミノ)−[2,3’−ビインドリニリデン]−2’−オンヒドロクロリド(化合物27)、
(2Z,3E)−3−((2−(ピペラジン−1−イル)エトキシ)イミノ)−[2,3’−ビインドリニリデン]−2’−オンジヒドロクロリド(化合物28)、
(2Z,3E)−3−((2−(4−メチルピペラジン−1−イル)エトキシ)イミノ)−[2,3’−ビインドリニリデン]−2’−オンジヒドロクロリド(化合物29)、
(2Z,3E)−3−((2−(ピペリジン−1−イル)エトキシ)イミノ)−[2,3’−ビインドリニリデン]−2’−オンヒドロクロリド(化合物30)、
(2Z,3E)−3−((2−(ピロリジン−1−イル)エトキシ)イミノ)−[2,3’−ビインドリニリデン]−2’−オンヒドロクロリド(化合物31)、
(2Z,3E)−3−((2−(ピペリジン−4−イルアミノ)エトキシ)イミノ)−[2,3’−ビインドリニリデン]−2’−オンジヒドロクロリド(化合物32)、
(2Z,3E)−5’−フルオロ−3−((2−(ピペラジン−1−イル)エトキシ)イミノ)−[2,3’−ビインドリニリデン]−2’−オンジヒドロクロリド(化合物33)、
(2Z,3E)−5’−フルオロ−3−((2−(4−メチルピペラジン−1−イル)エトキシ)イミノ)−[2,3’−ビインドリニリデン]−2’−オンジヒドロクロリド(化合物34)、
(2Z,3E)−5’−フルオロ−3−((2−(ピペリジン−1−イル)エトキシ)イミノ)−[2,3’−ビインドリニリデン]−2’−オンヒドロクロリド(化合物35)、
(2Z,3E)−5’−フルオロ−3−((2−(ピロリジン−1−イル)エトキシ)イミノ)−[2,3’−ビインドリニリデン]−2’−オンヒドロクロリド(化合物36)、
(2Z,3E)−5’−フルオロ−3−((2−(ピペリジン−4−イルアミノ)エトキシ)イミノ)−[2,3’−ビインドリニリデン]−2’−オンジヒドロクロリド(化合物37)、
(2Z,3E)−5'−クロロ−3−((2−(ピペラジン−1−イル)エトキシ)イミノ)−[2,3’−ビインドリニリデン]−2'−オンジヒドロクロリド(化合物38)、
(2Z,3E)−5'−クロロ−3−((2−(4−メチルピペラジン−1−イル)エトキシ)イミノ)−[2,3’−ビインドリニリデン]−2'−オンジヒドロクロリド(化合物39)、
(2Z,3E)−5'−ブロモ−3−((2−(ピペラジン−1−イル)エトキシ)イミノ)−[2,3’−ビインドリニリデン]−2'−オンジヒドロクロリド(化合物40)、
(2Z,3E)−5'−ブロモ−3−((2−(4−メチルピペラジン−1−イル)エトキシ)イミノ)−[2,3’−ビインドリニリデン]−2'−オンジヒドロクロリド(化合物41)、
(2Z,3E)−5'−ヨード−3−((2−(ピペラジン−1−イル)エトキシ)イミノ)−[2,3’−ビインドリニリデン]−2'−オンジヒドロクロリド(化合物42)、
(2Z,3E)−5'−ヨード−3−((2−(4−メチルピペラジン−1−イル)エトキシ)イミノ)−[2,3’−ビインドリニリデン]−2'−オンジヒドロクロリド(化合物43)、
(2Z,3E)−3−((2−(ピペラジン−1−イル)エトキシ)イミノ)−5'−(トリフルオロメトキシ)−[2,3’−ビインドリニリデン]−2'−オンジヒドロクロリド(化合物44)、
(2Z,3E)−3−((2−(4−メトキシピペラジン−1−イル)エトキシ)イミノ)−5'−(トリフルオロメトキシ)−[2,3’−ビインドリニリデン]−2'−オンジヒドロクロリド(化合物45)、
(2Z,3E)−5'−メトキシ−3−((2−(ピペラジン−1−イル)エトキシ)イミノ)−[2,3’−ビインドリニリデン]−2'−オンジヒドロクロリド(化合物46)、及び
(2Z,3E)−5'−メトキシ−3−((2−(4−メチルピペラジン−1−イル)エトキシ)イミノ)−[2,3’−ビインドリニリデン]−2'−オンジヒドロクロリド(化合物47)からなる群から選択されるいずれか1つの化合物であることを特徴とする請求項1に記載の化合物、その薬学的に許容される塩、溶媒和物又は水和物。 - 前記化学式(1)で表される化合物は、FLT3阻害に対するIC50値が100nM以下であることを特徴とする請求項1〜8のいずれか一項に記載の化合物、その薬剤学的に許容される塩、溶媒和物又は水和物。
- 前記化学式(1)で表される化合物は、FLT3阻害に対するIC50値が20nM以下であることを特徴とする請求項1〜8のいずれか一項に記載の化合物、その薬剤学的に許容される塩、溶媒和物又は水和物。
- (a)次の化学式(1)で表される化合物、その薬剤学的に許容される塩、溶媒和物又は水和物と、(b)薬学的に許容される担体とを含む、急性骨髄性白血病(Acute myeloid leukemia)又は転移性乳癌の予防又は治療用薬剤学的組成物。
- 前記R3は、化学式(3)又は(4)であることを特徴とする請求項11に記載の薬剤学的組成物。
- 前記化学式(1)で表される化合物は、
メチル−(2Z,3E)−2'−オキソ−3−((2−(ピペラジン−1−イル)エトキシ)イミノ)−[2,3’−ビインドリニリデン]−5'−カルボキシレートジヒドロクロリド(化合物4)、
メチル−(2Z,3E)−3−(ヒドロキシイミノ)−2’−オキソ−[2,3’−ビインドリニリデン]−5’−カルボキシレート(化合物1)、
メチル−(2Z,3E)−3−((2−ブロモエトキシ)イミノ)−2’−オキソ−[2,3’−ビインドリニリデン]−5’−カルボキシレート(化合物2)、
メチル−(2Z,3E)−3−((2−アミノエトキシ)イミノ)−2’−オキソ−[2,3’−ビインドリニリデン]−5'−カルボキシレートヒドロクロリド(化合物3)、
メチル−(2Z,3E)−3−((2−(4−メチルピペラジン−1−イル)エトキシ)イミノ)−2’−オキソ−[2,3’−ビインドリニリデン]−5'−カルボキシレートジヒドロクロリド(化合物5)、
メチル−(2Z,3E)−3−((2−モルホリノエトキシ)イミノ)−2’−オキソ−[2,3’−ビインドリニリデン]−5'−カルボキシレートヒドロクロリド(化合物6)、
(2Z,3E)−3−(ヒドロキシイミノ)−2’−オキソ−[2,3’−ビインドリニリデン]−5’−カルボン酸(化合物7)、
(2Z,3E)−3−((2−ブロモエトキシ)イミノ)−2’−オキソ−[2,3’−ビインドリニリデン]−5’−カルボン酸(化合物8)、
(2Z,3E)−3−((2−アミノエトキシ)イミノ)−2’−オキソ−[2,3’−ビインドリニリデン]−5'−カルボン酸ジヒドロクロリド(化合物9)、
(2Z,3E)−2’−オキソ−3−((2−(ピペラジン−1−イル)エトキシ)イミノ)−[2,3’−ビインドリニリデン]−5'−カルボン酸ジヒドロクロリド(化合物10)、
(2Z,3E)−3−((2−(4−メチルピペラジン−1−イル)エトキシ)イミノ)−2’−オキソ−[2,3’−ビインドリニリデン]−5'−カルボン酸ジヒドロクロリド(化合物11)、
(2Z,3E)−3−((2−モルホリノエトキシ)イミノ)−2’−オキソ−[2,3’−ビインドリニリデン]−5'−カルボキシレートヒドロクロリド(化合物12)、
(2Z,3E)−5−ヒドロキシ−3−(ヒドロキシイミノ)−5'−ニトロ−[2,3’−ビインドリニリデン]−2'−オン(化合物13)、
(2Z,3E)−5−ヒドロキシ−3−((2−(4−メチルピペラジン−1−イル)エトキシ)イミノ)−5'−ニトロ−[2,3’−ビインドリニリデン]−2'−オンジヒドロクロリド(化合物14)、
(2Z,3E)−3−((2−アミノエトキシ)イミノ)−5'−ニトロ−[2,3’−ビインドリニリデン]−2'−オンヒドロクロリド(化合物15)、
(2Z,3E)−5'−ニトロ−3−((2−(ピペラジン−1−イル)エトキシ)イミノ)−[2,3’−ビインドリニリデン]−2'−オンジヒドロクロリド(化合物16)、
(2Z,3E)−5−フルオロ−5'−ニトロ−3−((2−(ピペラジン−1−イル)エトキシ)イミノ)−[2,3’−ビインドリニリデン]−2'−オンジヒドロクロリド(化合物17)、
(2Z,3E)−5−フルオロ−3−((2−(4−メチルピペラジン−1−イル)エトキシ)イミノ)−5'−ニトロ−[2,3’−ビインドリニリデン]−2'−オンジヒドロクロリド(化合物18)、
(2Z,3E)−5−フルオロ−5'−ニトロ−3−((2−(ピペリジン−1−イル)エトキシ)イミノ)−[2,3’−ビインドリニリデン]−2'−オンヒドロクロリド(化合物19)、
(2Z,3E)−5−フルオロ−5'−ニトロ−3−((2−(ピロリジン−1−イル)エトキシ)イミノ)−[2,3’−ビインドリニリデン]−2'−オンヒドロクロリド(化合物20)、
(2Z,3E)−5,5’−ジフルオロ−3−((2−(ピペラジン−1−イル)エトキシ)イミノ)−[2,3’−ビインドリニリデン]−2’−オンジヒドロクロリド(化合物21)、
(2Z,3E)−5,5’−ジフルオロ−3−((2−(4−メチルピペラジン−1−イル)エトキシ)イミノ)−[2,3’−ビインドリニリデン]−2’−オンヒドロクロリド(化合物22)、
(2Z,3E)−5,5’−ジフルオロ−3−((2−(ピペリジン−1−イル)エトキシ)イミノ)−[2,3’−ビインドリニリデン]−2’−オンヒドロクロリド(化合物23)、
(2Z,3E)−5,5’−ジフルオロ−3−((2−(ピロリジン−1−イル)エトキシ)イミノ)−[2,3’−ビインドリニリデン]−2’−オンヒドロクロリド(化合物24)、
(2Z,3E)−3−((2−(4−アミノピペリジン−1−イル)エトキシ)イミノ)−5,5’−ジフルオロ−[2,3’−ビインドリニリデン]−2’−オンジヒドロクロリド(化合物25)、
(2Z,3E)−5,5’−ジフルオロ−3−((2−(ピペリジン−4−イルアミノ)エトキシ)イミノ)−[2,3’−ビインドリニリデン]−2’−オンジヒドロクロリド(化合物26)、
(2Z,3E)−5,5’−ジフルオロ−3−((2−モルホリノエトキシ)イミノ)−[2,3’−ビインドリニリデン]−2’−オンヒドロクロリド(化合物27)、
(2Z,3E)−3−((2−(ピペラジン−1−イル)エトキシ)イミノ)−[2,3’−ビインドリニリデン]−2’−オンジヒドロクロリド(化合物28)、
(2Z,3E)−3−((2−(4−メチルピペラジン−1−イル)エトキシ)イミノ)−[2,3’−ビインドリニリデン]−2’−オンジヒドロクロリド(化合物29)、
(2Z,3E)−3−((2−(ピペリジン−1−イル)エトキシ)イミノ)−[2,3’−ビインドリニリデン]−2’−オンヒドロクロリド(化合物30)、
(2Z,3E)−3−((2−(ピロリジン−1−イル)エトキシ)イミノ)−[2,3’−ビインドリニリデン]−2’−オンヒドロクロリド(化合物31)、
(2Z,3E)−3−((2−(ピペリジン−4−イルアミノ)エトキシ)イミノ)−[2,3’−ビインドリニリデン]−2’−オンジヒドロクロリド(化合物32)、
(2Z,3E)−5’−フルオロ−3−((2−(ピペラジン−1−イル)エトキシ)イミノ)−[2,3’−ビインドリニリデン]−2’−オンジヒドロクロリド(化合物33)、
(2Z,3E)−5’−フルオロ−3−((2−(4−メチルピペラジン−1−イル)エトキシ)イミノ)−[2,3’−ビインドリニリデン]−2’−オンジヒドロクロリド(化合物34)、
(2Z,3E)−5’−フルオロ−3−((2−(ピペリジン−1−イル)エトキシ)イミノ)−[2,3’−ビインドリニリデン]−2’−オンヒドロクロリド(化合物35)、
(2Z,3E)−5’−フルオロ−3−((2−(ピロリジン−1−イル)エトキシ)イミノ)−[2,3’−ビインドリニリデン]−2’−オンヒドロクロリド(化合物36)、
(2Z,3E)−5’−フルオロ−3−((2−(ピペリジン−4−イルアミノ)エトキシ)イミノ)−[2,3’−ビインドリニリデン]−2’−オンジヒドロクロリド(化合物37)、
(2Z,3E)−5'−クロロ−3−((2−(ピペラジン−1−イル)エトキシ)イミノ)−[2,3’−ビインドリニリデン]−2'−オンジヒドロクロリド(化合物38)、
(2Z,3E)−5'−クロロ−3−((2−(4−メチルピペラジン−1−イル)エトキシ)イミノ)−[2,3’−ビインドリニリデン]−2'−オンジヒドロクロリド(化合物39)、
(2Z,3E)−5'−ブロモ−3−((2−(ピペラジン−1−イル)エトキシ)イミノ)−[2,3’−ビインドリニリデン]−2'−オンジヒドロクロリド(化合物40)、
(2Z,3E)−5'−ブロモ−3−((2−(4−メチルピペラジン−1−イル)エトキシ)イミノ)−[2,3’−ビインドリニリデン]−2'−オンジヒドロクロリド(化合物41)、
(2Z,3E)−5'−ヨード−3−((2−(ピペラジン−1−イル)エトキシ)イミノ)−[2,3’−ビインドリニリデン]−2'−オンジヒドロクロリド(化合物42)、
(2Z,3E)−5'−ヨード−3−((2−(4−メチルピペラジン−1−イル)エトキシ)イミノ)−[2,3’−ビインドリニリデン]−2'−オンジヒドロクロリド(化合物43)、
(2Z,3E)−3−((2−(ピペラジン−1−イル)エトキシ)イミノ)−5'−(トリフルオロメトキシ)−[2,3’−ビインドリニリデン]−2'−オンジヒドロクロリド(化合物44)、
(2Z,3E)−3−((2−(4−メトキシピペラジン−1−イル)エトキシ)イミノ)−5'−(トリフルオロメトキシ)−[2,3’−ビインドリニリデン]−2'−オンジヒドロクロリド(化合物45)、
(2Z,3E)−5'−メトキシ−3−((2−(ピペラジン−1−イル)エトキシ)イミノ)−[2,3’−ビインドリニリデン]−2'−オンジヒドロクロリド(化合物46)、及び
(2Z,3E)−5'−メトキシ−3−((2−(4−メチルピペラジン−1−イル)エトキシ)イミノ)−[2,3’−ビインドリニリデン]−2'−オンジヒドロクロリド(化合物47)からなる群から選択されるいずれか1つの化合物であることを特徴とする請求項11に記載の薬剤学的組成物。
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KR102278176B1 (ko) | 2020-02-20 | 2021-07-16 | 한국과학기술원 | Ash1l 히스톤 메틸화 효소 활성을 억제하는 벤조디옥솔 유도체 화합물을 포함하는 백혈병의 예방 또는 치료용 조성물 |
KR20210106155A (ko) | 2020-02-20 | 2021-08-30 | 한국과학기술원 | Ash1l 히스톤 메틸화 효소 활성을 억제하는 페닐카르보노히드라조노일 디시아나이드 유도체 화합물을 포함하는 백혈병의 예방 또는 치료용 조성물 |
KR102325607B1 (ko) | 2020-02-20 | 2021-11-12 | 한국과학기술원 | Ash1l 히스톤 메틸화 효소 활성을 억제하는 벤조퓨란-피라졸 유도체 화합물을 포함하는 백혈병의 예방 또는 치료용 조성물 |
US20220079934A1 (en) * | 2020-09-17 | 2022-03-17 | Arog Pharmaceuticals, Inc. | Crenolanib for treating pain |
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WO2019088677A1 (ko) | 2019-05-09 |
US11370779B2 (en) | 2022-06-28 |
EP3705474A1 (en) | 2020-09-09 |
US20200270229A1 (en) | 2020-08-27 |
KR20190049584A (ko) | 2019-05-09 |
JP7005779B2 (ja) | 2022-02-10 |
RU2763346C2 (ru) | 2021-12-28 |
CA3080900C (en) | 2022-10-25 |
BR112020008499A2 (pt) | 2020-10-20 |
RU2020115581A3 (ja) | 2021-12-02 |
EP3705474A4 (en) | 2021-06-09 |
AU2018358582A1 (en) | 2020-05-07 |
PH12020550491A1 (en) | 2021-01-11 |
RU2020115581A (ru) | 2021-12-02 |
KR102247795B1 (ko) | 2021-05-04 |
KR102247795B9 (ko) | 2023-04-12 |
CN111542513A (zh) | 2020-08-14 |
AU2018358582B2 (en) | 2021-06-10 |
MX2020004374A (es) | 2020-11-11 |
CA3080900A1 (en) | 2019-05-09 |
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