JP7483032B2 - 新規ケルセチンレドックス誘導体及びbet阻害剤としての用途 - Google Patents
新規ケルセチンレドックス誘導体及びbet阻害剤としての用途 Download PDFInfo
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- JP7483032B2 JP7483032B2 JP2022557632A JP2022557632A JP7483032B2 JP 7483032 B2 JP7483032 B2 JP 7483032B2 JP 2022557632 A JP2022557632 A JP 2022557632A JP 2022557632 A JP2022557632 A JP 2022557632A JP 7483032 B2 JP7483032 B2 JP 7483032B2
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- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 239000012286 potassium permanganate Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000002953 preparative HPLC Methods 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 150000003244 quercetin derivatives Chemical class 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 238000006479 redox reaction Methods 0.000 description 1
- 230000006697 redox regulation Effects 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 230000014493 regulation of gene expression Effects 0.000 description 1
- 230000026267 regulation of growth Effects 0.000 description 1
- 230000022532 regulation of transcription, DNA-dependent Effects 0.000 description 1
- 230000008844 regulatory mechanism Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 238000013207 serial dilution Methods 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 230000002381 testicular Effects 0.000 description 1
- 210000001550 testis Anatomy 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- 230000000451 tissue damage Effects 0.000 description 1
- 231100000827 tissue damage Toxicity 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- 235000002374 tyrosine Nutrition 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 238000012800 visualization Methods 0.000 description 1
Images
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- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- A61K31/00—Medicinal preparations containing organic active ingredients
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- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
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- 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
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
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- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/42—Oxazoles
- A61K31/423—Oxazoles condensed with carbocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- 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
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- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
- C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
- C07D311/28—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only
- C07D311/30—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only not hydrogenated in the hetero ring, e.g. flavones
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Description
環Xは、
;または置換または非置換のアリールであり、
ここで、A、B、C、及びDは、それぞれ独立して、C、C(=O)、N、O、Sまたは不在であり、
Yは、C、C(=O)、N、OまたはSであり、
Zは、CR5またはNR5であり、
----は、それぞれ不在または単結合であり、
R1、R2及びR5は、それぞれ独立して、H、ハロ、シアノ、アルキル、アルケニル、アルキニル、-C(=O)Ra、-C(=O)N(Ra)(Rb)、-C(=O)ORa、-N(Ra)(Rb)、-N(Ra)C(=O)Rb、-N(Ra)S(=O)Rb、-N(Ra)S(=O)2Rb、-NO2、-ORa、-OC(=O)Ra、-SRa、-S(=O)Ra、-S(=O)N(Ra)(Rb)、-S(=O)2Ra、-S(=O)2N(Ra)(Rb)、シクロアルキル、ヘテロシクロアルキル、アリール、またはヘテロアリールであり、
R3は、H、アルキル、及び-ORaからなる群から選択される同一または互いに異なる少なくとも1つであってもよく、
R4は、H、アルキル、アルケニル、及びアルキニルからなる群から選択される同一または互いに異なる少なくとも1つであってもよく、
Ra及びRbは、それぞれ独立して、H、ハロ、シアノ、アルキル、シクロアルキル、またはヘテロシクロアルキルである。
は、残基または置換基「R」が骨格構造に結合していることを示すために用いられる。
環Xは、
;または置換または非置換のアリールであり、
ここで、A、B、C、及びDは、それぞれ独立して、C、C(=O)、N、O、Sまたは不在であり、
Yは、C、C(=O)、N、OまたはSであり、
Zは、CR5またはNR5であり、
----は、それぞれ不在または単結合であり、
R1、R2及びR5は、それぞれ独立して、H、ハロ、シアノ、アルキル、アルケニル、アルキニル、-C(=O)Ra、-C(=O)N(Ra)(Rb)、-C(=O)ORa、-N(Ra)(Rb)、-N(Ra)C(=O)Rb、-N(Ra)S(=O)Rb、-N(Ra)S(=O)2Rb、-NO2、-ORa、-OC(=O)Ra、-SRa、-S(=O)Ra、-S(=O)N(Ra)(Rb)、-S(=O)2Ra、-S(=O)2N(Ra)(Rb)、シクロアルキル、ヘテロシクロアルキル、アリール、またはヘテロアリールであり、
R3は、H、アルキル、及び-ORaからなる群から選択される同一または互いに異なる少なくとも1つであってもよく、
R4は、H、アルキル、アルケニル、及びアルキニルからなる群から選択される同一または互いに異なる少なくとも1つであってもよく、
Ra及びRbは、それぞれ独立して、H、ハロ、シアノ、アルキル、シクロアルキル、またはヘテロシクロアルキルである。
前記環Xは、
または
であり、
R3は、H、C1~C6のアルキル、及び-ORaからなる群から選択される同一または互いに異なる少なくとも1つであってもよく、ここで、Raは、H、C1~C6のアルキル、シクロアルキル、あるいはN、O、またはSから選択されるヘテロ原子を含む3~10員のヘテロシクロアルキルであり、
R6及びR7は、それぞれ独立して、H、またはC1~C6のアルキルであってもよい。
Yは、NまたはOであり、
Zは、CR5またはNR5であり、
R1、R2及びR5は、それぞれ独立して、H、C1~C6のアルキル、OH、または-O-C1~C6のアルキルであってもよい。
前記環Xは、
または
であり、
R8は、H、またはC1~C6のアルキルであり、
R9、R10またはR11は、それぞれ独立して、H、C1~C6のアルキル、または-ORaであり、ここで、Raは、H、C1~C6のアルキル、またはOのヘテロ原子を含む3~10員のヘテロシクロアルキルであってもよい。
[反応式]
3-(1H-ベンゾジイミダゾール-5-イル)-1-(2-ヒドロキシ-4,6-ジメトキシフェニル)プロパ-2-エン-1-オンの調製
1-(2-ヒドロキシ-4,6-ジメトキシフェニルケテン(500mg、2.55mmol、1eq)をDMF(15mL)に溶かし、次いで0℃で水酸化ナトリウム(254.84mg、6.37mmol、60%の純度(purity)、2.5eq)と、1H-ベンゾジイミダゾール-5-カルボアルデヒド(409.69mg、2.80mmol、1.1eq)を加え、混合物を25℃で12時間にかけて撹拌した。反応が終了すると、蒸留水と酢酸エチルで抽出した。無水硫酸ナトリウムを用いて有機層を乾燥し、濃縮し、それからカラムクロマトグラフィーで精製して中間体3(300mg、924.98umol、36.30%の収率(yield))を得た。
LCMS:RT=0.821min、m/z:325.2(M+H)+
2-(1H-ベンゾイミダゾール-5-イル)-3-ヒドロキシ-5,7-ジメトキシ-4H-クロメン-4-ノンの合成
3-(1H-ベンゾジイミダゾール-5-イル)-1-(2-ヒドロキシ-4,6-ジメトキシフェニル)プロパ-2-エン-1-オン(270mg、832.49umol、1eq)をメタノール(60mg)/水(30mL)に溶かし、0℃で水酸化ナトリウム(170.09mg、4.25mmol、5.11eq)及び過酸化水素(288.00mg、2.54mmol、244.07uL、30%の純度、3.05eq)を加え、混合物を25℃で12時間にかけて撹拌した。反応が終了すると、蒸留水で希釈し、pH5に調整し、次いで酢酸エチルで抽出した。無水硫酸ナトリウムを用いて有機層を乾燥し、濃縮して中間体4(120mg)を得た。
LCMS:RT=0.650min、m/z:339.0(M+H)+
2-(1H-ベンゾジイミダゾール-5-イル)-3,5,7-トリヒドロキシ-4H-クロメン-4-オン(BBC0109)の調製
2-(1H-ベンゾイミダゾール-5-イル)-3-ヒドロキシ-5,7-ジメトキシ-4H-クロメン-4-オン(50mg、147.79umol、1当量)をジクロロエタン(3mL)に溶解し、次いで、ここに三臭化ホウ素(370.25mg、1.48mmol、142.40μL、10eq)を加え、それから60℃で12時間にかけて撹拌した。反応が終了すると、メタノールを加えて濃縮し、次いでprep-HPLCで精製して化合物1(3.23mg、9.67umol、3.27%の収率、92.9%の純度)を得た。
1H NMR(400MHz、メタノール-d4)δppm 8.60(1H、s)、8.33(1H、s)、8.15-8.22(1H、m)、7.77(1H、d、J=8.4Hz)、6.49(1H、d、J=2.0Hz)、6.24(1H、d、J=2.0Hz)
LCMS:RT=2.049min、m/z:311.0(M+H)+
[反応式]
2-オキソ-1,3-ジヒドロベンズイミダゾール-5-カルボン酸1(196.0mg、1.1mmol、2.0eq)から5-(3,5,7-トリヒドロキシ-4-オキソ-クロメン-2-イル)-1,3-ジヒドロベンズイミダゾール-2-one(BBC0110)(2.64mg、7.3umol、3.6%の収率、90.5%の純度)を前記反応式から得た。
LCMS:RT=2.270min、m/z:327.0(M+H)+
1HNMR(400MHz、DMSO-d6)δppm 10.71-10.88(1H、m) 7.78-7.87(2H、m) 7.08(1H、d、J=8.4Hz) 6.39(1H、d、J=1.6Hz) 6.15(1H、d、J=2.0Hz)。
[反応式1]
[反応式2]
[反応式3]
前記反応式1~3のうちいずれか1つの反応式でBBC0111の化合物を調製した。
[反応式]
2-アミノ-5-ブロモ-フェノール1(1.0g、5.32mmol、1.0eq)から6-(3,5,7-トリヒドロキシ-4-オキソ-クロメン-2-イル)-3H-1,3-ベンズオキサゾール-2-オン(BBC0113)(4.6mg、12.8umol、18.2%の収率、91%の純度)を得た。
LCMS:RT=2.447min、m/z:328.0(M+H)+
1H NMR(400MHz、MeOD)δppm 8.11(2H、s)、7.22(1H、br d、J=8.0Hz)、6.44(1H、s)、6.20(1H、s)
[反応式]
1H-インドール-5-カルボン酸1(92.2mg、572.0umol、2.0eq)から3,5,7-トリヒドロキシ-2-(1H-インドール-5-イル)クロメン-4-オン(BBC0114)(2.38mg、7.16umol、4.6%の収率、93%の純度)を得た。
LCMS:RT=2.666min、m/z:310.0(M+H)+
1H NMR(400MHz、MeOD)δppm 8.50(1H、d、J=1.2Hz) 7.99(1H、dd、J=8.8、1.6Hz) 7.50(1H、d、J=8.8Hz) 7.32(1H、d、J=3.2Hz) 6.58(1H、dd、J=3.2、0.8Hz)6.45(1H、d、J=2.0Hz) 6.20(1H、d、J=2.0Hz)
[反応式]
1H-インドール-6-カルボン酸1(106.4mg、660.1umol、2.0eq)から3,5,7-トリヒドロキシ-2-(1H-インドール-6-イル)クロメン-4-オン(BBC0115)(4.73mg、13.8umol、8.0%の収率、90.4%の純度)を得た。
LCMS:RT=2.711min、m/z:310.0(M+H)+
1H NMR(400MHz、DMSO-d6)δppm 12.52(1H、s) 11.45(1H、br s) 10.81(1H、s) 9.48(1H、s) 8.39(1H、s) 7.82(1H、dd、J=8.4、1.6Hz) 7.69(1H、d、J=8.4Hz) 7.54(1H、t、J=2.8Hz) 6.45-6.54(2H、m) 6.21(1H、d、J=2.0Hz)
[反応式1]
[反応式2]
[反応式3]
[反応式4]
前記反応式1~4のうちいずれか1つの方法で化合物7(BBC0116)を調製した。
[反応式]
クロメン-6-カルボン酸1(55mg、308.67umol、2eq)から2-クロメン-6-イル-3,5,7-トリヒドロキシ-クロメン-4-オン(10.85mg、32.55umol、13.87%の収率、97.893%の純度)を得た。
LCMS:RT=2.857min、m/z:327.0(M+H)+
1H NMR(400MHz、DMSO):δ(ppm) 12.44(1H、s)、7.95-7.84(2H、m)、6.88(1H、d、J=8.40Hz)、6.43(1H、d、J=2.00Hz)、6.18(1H、d、J=2.00Hz)、4.32-4.12(2H、m)、2.82(2H、t、J=6.00Hz)、2.04-1.83(2H、m)
[反応式]
ベンゾフラン-5-カルボン酸(143mg、881.94umol、2eq)と2-ベンジルオキシ-1-(2,4-ジベンジルオキシ-6-ヒドロキシフェニル)エタノン(200mg、440.0umol、1eq)から2-(ベンゾフラン-5-イル)-3,5,7-トリヒドロキシ-クロメン-4-オン(BBC0310)(19.45mg、61.51umol、14.88%の収率、98.112%の純度)を得た。
LCMS:RT=2.834min、m/z:311.0(M+H)+
1H NMR(400MHz、DMSO):δ(ppm)8.52(1H、s)、8.16(1H、d、J=8.8Hz)、8.10(1H、d、J=2.40Hz)、7.77(1H、d、J=8.80Hz)、7.12(1H、d、J=1.2Hz)、6.48(1H、d、J=2.0Hz)、6.20(1H、d、J=2.00Hz)。
[反応式]
2-ベンジルオキシ-1-(2,4-ジベンジルオキシ-6-ヒドロキシ-フェニル)エタノン(200mg、440.03umol、1eq)と、2,3-ジヒドロベンゾフラン-5-カルボン酸(148.00mg、901.57umol、2.05eq)から2-(2,3-ジヒドロベンゾフラン-5-イル)-3,5,7-トリヒドロキシ-クロメン-4-オン(BBC0311)(41.24mg、126.61umol、36.88%の収率、95.867%の純度)を得た。
LCMS:RT=2.436min、m/z:313.0(M+H)+
1H NMR(400MHz、MeOD):δ(ppm) 8.09(1H、s)、8.01(1H、dd、J=8.8、1.6Hz)、6.85(1H、d、J=8.8Hz)、6.40(1H、d、J=2.0Hz)、6.18(1H、d、J=2.4Hz)、4.63(2H、t、J=8.8Hz)、3.27(2H、s)。
[反応式]
ベンゾフラン-6-カルボン酸(300.0mg、1.85mmol、1.0eq)から2-(2,3-ジヒドロベンゾフラン-6-イル)-3,5,7-トリヒドロキシ-クロメン-4-オン(BBC0312)(29.12mg、88.7umol、36.9%の収率、95.1%の純度)を得た。
LCMS:RT=2.762min、m/z:313.1(M+H)+
1H NMR(400MHz、DMSO-d6)δppm 12.36(1H、s)10.85(1H、br s)9.61(1H、br s)7.67(1H、dd、J=8.0、1.2Hz)7.53(1H、d、J=1.2Hz)7.39(1H、d、J=8.0Hz)6.46(1H、d、J=2.0Hz)6.20(1 H、d、J=2.0Hz)4.58(2H、t、J=8.8)Hz)3.24(2H、t、J=8.8Hz)。
[反応式]
2-(3,4-ジヒドロキシフェニル)-3,5,7-トリヒドロキシ-クロメン-4-オン(15.0g、49.6mmol、1.0eq)から2-(ベンゾフラン-6-イル)-3,5,7-トリヒドロキシ-クロメン-4-オン(BBC0313)(13mg、40.7umol、26.3%の収率、97.1%の純度)を得た。
LCMS:RT=2.836min、m/z:97.1(M+H)+
1H NMR(400MHz、DMSO-d6)δppm 12.39(1H、s)8.43(1H、s)8.16(1H、d、J=2.0Hz)8.11(1H、dd、J=8.4、1.6Hz)7.82(1H、d、J=8.4Hz)7.07(1H、dd、J=2.0、0.8Hz)6.52(1H、d、J=2.0Hz)6.22(1H、d、J=2.0Hz)。
[反応式]
2,3-ジヒドロベンゾフラン-5-カルボアルデヒド1(500mg、3.37mmol、1eq)から5,7-ジメトキシ-2-(7-メチル-2,3-ジヒドロベンゾフラン-5-イル)-3H-キナゾリン-4-オン(BBC0406)(13mg、38.11umol、4.15%の収率、99.2%の純度)を得た。
LCMS:RT=2.200min、m/z:339.1(M+H)+
1H NMR(400MHz、クロロホルム-d)δppm 8.98(1H、br s)、7.71(1H、s)、7.60(1H、s)、6.80(1H、d、J=2.4Hz)6.44(1H、d、J=2.4Hz)、4.68(2H、t、J=8.8Hz)、3.98(3H、s)、3.92(3H、s)、3.30(2H、t、J=8.8Hz)、2.28(3H、s)。
[反応式]
2,3-ジヒドロベンゾフラン-5-カルボアルデヒド(1g、6.75mmol、1eq)から5,7-ジメトキシ-2-(7-メチルベンゾフラン-5-イル)-3H-キナゾリン-4-オン(BBC0407)(6.77mg、19.14umol、43.17%の収率、95.070%の純度)を得た。
LCMS:RT=2.264min、m/z:337.1(M+H)+
1H NMR(400MHz、MeOD):δ(ppm) 8.15(1H、s)、7.91(1H、d、J=2.0Hz)、7.85(1H、s)、7.00(1H、d、J=2.0Hz)、6.86(1H、d、J=2.0Hz)、6.61(1H、d、J=2.0Hz)、3.96(6H、m)、2.64(3H、s)。
[反応式]
3,4-ジヒドロキシベンズアルデヒド(1.0g、7.24mmol、1.0eq)から3,5,7-トリヒドロキシ-2-[3-ヒドロキシ-4-(オキセタン-3-イルロキシ)フェニル]クロメン-4-オン(BBC0301)(5.57mg、15.3umol、19%の収率、98.3%の純度)を得た。
LCMS:RT=2.465min、m/z:359.0(M+H)+
1H NMR(400MHz、DMSO-d6)δppm 12.43(1H、s)10.82(1H、s)9.47-9.54(2H、m)7.72(1H、d、J=2.4Hz)7.58(1H、dd、J=8.8、2.4Hz)6.74(1H、d、J=8.8Hz)6.42(1H、d、J=2.0Hz)6.20(1H、d、J=2.0Hz)5.32(1H、t、J=5.6Hz)4.94(2H、t、J=6.8Hz)4.61(2H、dd、J=7.6、5.2Hz)。
[反応式]
4-ヒドロキシベンズアルデヒド1(65mg、532.26umol、1.21eq)から3,5,7-トリヒドロキシ-2-[4-(オキセタン-3-イルオキシ)フェニル]クロメン-4-オン(1.69mg、4.49umol、46.95%の収率、91%の純度)を得た。
LCMS:RT=2.792min、m/z:343.1(M+H)+
1H NMR(400MHz、CD3OD)δ 8.19(2H、d、J=8.8Hz)、6.91(2H、d、J=8.8Hz)、6.41(1H、d、J=2.0Hz)、6.19(1H、d、J=2.0Hz)、5.41-5.35(1H、m)、5.08-5.04(2H、m)、6.74-4.69(2H、m)。
[反応式]
3,4-ジヒドロキシベンズアルデヒド(200.0mg、1.45mmol、1.0eq)から3,5,7-トリヒドロキシ-2-[4-ヒドロキシ-3-(オキセタン-3-イルロキシ))フェニル]クロメン-4-オン(BBC0303)(5.11mg、13.41umol、9.6%の収率、94%の純度)を得た。
LCMS:RT=2.471min、m/z:359.0(M+H)+
1H NMR(400MHz、DMSO-d6)δppm 10.79(1H、s)9.93(1H、s)9.46(1H、s)7.70(1H、dd、J=8.4、2.0Hz)7.45(1H、d、J=2.0Hz)6.99(1H、d、J=8.4Hz)6.48(1H、d、J=2.0Hz)6.19(1H、d、J=2.0Hz)5.29(1H、t、J=5.6Hz)4.91(2H、t、J=6.8Hz)4.66(2H、dd、J=7.6、5.6Hz)。
[反応式]
3-ブロモ-4-ヒドロキシ-5-メトキシ-ベンズアルデヒド1(2.0g、8.66mmol、1.7mL、1.0eq)から3,5,7-トリヒドロキシ-2-[3-ヒドロキシ-5-メチル-4-(オキセタン-3-イルオキシ)フェニル]クロメン-4-オン(BBC0305)(6mg、15.79umol、98%の純度)を得た。
LCMS:RT=2.607min、m/z:373.1(M+H)+
1H NMR(400MHz、DMSO-d6)δppm 12.31-12.49(1H、m) 9.65-9.90(1H、m) 7.59(1H、d、J=2.0Hz) 7.45(1H、d、J=1.6Hz) 6.39(1H、d、J=2.0Hz) 6.18(1H、d、J=2.0Hz) 5.14(1H、t、J=5.6Hz) 4.73-4.81(2H、m) 4.64-4.71(2H、m) 2.24(3H、s)。
[反応式]
4-ヒドロキシ-3,5-ジメチル-ベンズアルデヒド1(1g、6.66mmol、1eq)から2-[3,5-ジメチル-4-(オキセタン-3-イルオキシ)フェニル]-3,5,7-トリヒドロキシ-クロメン-4-オン(BBC0306)(23.28mg、61.68umol、15.81%の収率、98.128%の純度)を得た。
LCMS:RT=2.876min、m/z:371.0(M+H)+
1H NMR(400MHz、DMSO):δ(ppm) 7.85(2H、s)、6.44(1H、d、J=2.00Hz)、6.18(1H、d、J=2.00Hz)、4.94(1H、q、J=6.20Hz)、4.83(2H、t、J=6.40Hz)、4.80-4.76(2H、m)、2.23(6H、s)。
[反応式]
3-ブロモ-4-ヒドロキシ-5-メトキシ-ベンズアルデヒド1(2.0g、8.66mmol、1.7mL、1.0eq)から3,5,7-トリメトキシ-2-[4-ヒドロキシ-3-メチル-5-(オキセタン-3-イルオキシ)フェニル]クロメン-4-オン(BBC0307)(5.99mg、15.0umol、6.9%の収率、93.5%の純度)を得た。
LCMS:RT=2.654min、m/z:373.1(M+H)+
1H NMR(400MHz、DMSO-d6)δppm 12.44(1H、br d、J=1.6Hz) 7.62(1H、s) 7.31(1H、s) 6.47(1H、d、J=2.0Hz) 6.17(1H、d、J=2.0Hz) 5.30(1H、br t、J=5.6Hz) 4.91(2H、t、J=6.8Hz) 4.65-4.72(2H、m) 2.22(3H、s)。
[反応式]
1-(2,6-ジヒドロキシフェニル)エタノン1(1.0g、6.57mmol、1.0eq)から2-(3,4-ジヒドロキシフェニル)-3,5-ジヒドロキシ-クロメン-4-オン(BBC0104)(19mg、64.89umol、52.48%の収率、97.75%の純度)を得た。
LCMS:RT=0.735min、m/z:287(M+H)+
1H NMR(400MHz、DMSO-d6)δppm 12.41(1H、s)、9.60(2H、br s)、9.35(1H、br s)、7.74(1H、d、J=2.0Hz)、7.58-7.65(2H、m)、7.12(1H、d、J=8.0Hz)、6.91(1H、d、J=8.0Hz)、6.76(1H、d、J=8.0Hz)。
1-(2,4-ジヒドロキシフェニル)エタノン1(1.0g、6.57mmol、847.5uL、1.0eq)から2-(3,4-ジヒドロキシフェニル)-3,7-ジヒドロキシ-クロメン-4-オン(BBC0105)(12.0mg、39.95umol、40.4%の収率、95.3%の純度)を得た。
LCMS:RT=3.420min、m/z:287.0(M+H)+
1H NMR(400MHz、メタノール-d4)δppm 7.99(1H、d、J=9.2Hz) 7.77(1H、d、J=2.0Hz)7.67(1H、dd、J=8.4、2.00Hz) 6.88-6.95(3H、m)。
比較例1~3の化合物をWUXI APPTEC(SHANGHAI)CO.LTDから購入し、本発明の新規ケルセチン化合物とBET阻害効果を比較した。
本発明による新規化合物のBETタンパク質ファミリーの一つであるBRD2(BD1、BD2、BD1+BD2)、BRD3(BD1、BD2、BD1+BD2)、BRD4(BD1、BD2、BD1+BD2)のブロモドメインとテトラアセチル化ヒストンH4のペプチドとの間の相互作用抑制能力を評価するために、以下の実験を行った。
BETタンパク質中のBRD2タンパク質に対する本発明の化合物及び比較例の化合物の結合抑制効果を確認するために、以下のような実験を行った。
試験例1と同様の方法でBRD3(BD1、BD2、BD1+BD2)タンパク質に対する本発明の化合物及び比較例の化合物の結合抑制効果を確認するための実験を行った。その結果を表2に示す。
試験例1と同様の方法でBRD4(BD1、BD2、BD1+BD2)タンパク質に対する本発明の化合物及び比較例の化合物の結合抑制効果を確認するための実験を行った。その結果を表3、図3及び4に示す。
本開示は以下の実施形態を含む。
<1>
下記化学式1で表される化合物またはその薬学的に許容される塩:
式中、
環Xは、
;または置換または非置換のアリールであり、
ここで、A、B、C、及びDは、それぞれ独立して、C、C(=O)、N、O、Sまたは不在であり、
Yは、C、C(=O)、N、OまたはSであり、
Zは、CR 5 またはNR 5 であり、
----は、それぞれ不在または単結合であり、
R 1 、R 2 及びR 5 は、それぞれ独立して、H、ハロ、シアノ、アルキル、アルケニル、アルキニル、-C(=O)Ra、-C(=O)N(Ra)(Rb)、-C(=O)ORa、-N(Ra)(Rb)、-N(Ra)C(=O)Rb、-N(Ra)S(=O)Rb、-N(Ra)S(=O) 2 Rb、-NO 2 、-ORa、-OC(=O)Ra、-SRa、-S(=O)Ra、-S(=O)N(Ra)(Rb)、-S(=O) 2 Ra、-S(=O) 2 N(Ra)(Rb)、シクロアルキル、ヘテロシクロアルキル、アリール、またはヘテロアリールであり、
R 3 は、H、アルキル、及び-ORaからなる群から選択される同一または互いに異なる少なくとも1つであってもよく、
R 4 は、H、アルキル、アルケニル、及びアルキニルからなる群から選択される同一または互いに異なる少なくとも1つであってもよく、
Ra及びRbは、それぞれ独立して、H、ハロ、シアノ、アルキル、シクロアルキル、またはヘテロシクロアルキルである。
<2>
前記環Xは、
または
であり、
R 3 は、H、C 1 ~C 6 のアルキル、及び-ORaからなる群から選択される同一または互いに異なる少なくとも1つであってもよく、ここで、Raは、H、C 1 ~C 6 のアルキル、シクロアルキル、あるいはN、O、またはSから選択されるヘテロ原子を含む3~10員のヘテロシクロアルキルであり、
R 6 及びR 7 は、それぞれ独立して、H、またはC 1 ~C 6 のアルキルであることを特徴とする、<1>に記載の化学式1で表される化合物またはその薬学的に許容される塩。
<3>
Yは、NまたはOであり、
Zは、CR 5 またはNR 5 であり、
R 1 、R 2 及びR 5 は、それぞれ独立して、H、C 1 ~C 6 のアルキル、OH、または-O-C 1 ~C 6 のアルキルであることを特徴とする、<2>に記載の化学式1で表される化合物またはその薬学的に許容される塩。
<4>
前記環Xは、
または
であり、
R 8 は、H、またはC 1 ~C 6 のアルキルであり、
R 9 、R 10 及びR 11 は、それぞれ独立して、H、C 1 ~C 6 のアルキル、または-ORaであり、ここで、Raは、H、C 1 ~C 6 のアルキル、またはOのヘテロ原子を含む3~10員のヘテロシクロアルキルであることを特徴とする、<3>に記載の化学式1で表される化合物またはその薬学的に許容される塩。
<5>
下記化合物からなる群から選択される化合物、またはその薬学的に許容される塩:
及び
。
<6>
<1>ないし<5>のいずれか一項に記載の化合物またはその薬学的に許容される塩を含む、BET(Bromodomain Extra-Terminal)タンパク質関連疾患を予防または治療するための薬学的組成物。
<7>
前記BETタンパク質関連疾患が、癌と、自己免疫または炎症性疾患と、代謝性疾患と、ウイルス性疾患とからなる群から選択される少なくとも1つであることを特徴とする、<6>に記載の薬学的組成物。
<8>
前記癌が、血液癌、多発性骨髄腫、急性骨髄性白血病、悪性リンパ腫、再生不良性貧血、胸腺癌、卵巣癌、子宮頸癌、乳癌、大腸癌、肝臓癌、胃癌、膵臓癌、結腸癌、腹膜転移癌、皮膚癌、膀胱癌、前立腺癌、甲状腺癌、肺癌、骨肉腫、線維性腫瘍、及び脳腫瘍からなる群から選択される少なくとも1つであることを特徴とする、<7>に記載の薬学的組成物。
<9>
前記自己免疫または炎症性疾患が、慢性関節リウマチ、全身性エリテマトーデス、多発性硬化症、1型糖尿病、甲状腺機能亢進症、筋無力症、クローン病、強直性脊椎炎、乾癬、自己免疫性悪性貧血及びシェーグレン症候群、アレルギー、アレルギー性鼻炎、関節炎、喘息、慢性閉塞性肺疾患、変性関節疾患、皮膚炎、臓器拒絶、湿疹、肝炎、炎症性腸疾患、敗血症、敗血症症候群、敗血症ショック、及び非アルコール性脂肪肝炎からなる群から選択される少なくとも1つであることを特徴とする、<7>に記載の薬学的組成物。
<10>
前記代謝性疾患が、高トリグリセリド血症、肥満、高脂血症、過インスリン血症、過血糖症、動脈硬化症、高血圧、2型糖尿病、及びインスリン抵抗性疾患からなる群から選択されるいずれか1つ以上である、<7>に記載の薬学的組成物。
<11>
前記ウイルス性疾患が、ポリオ、急性出血性結膜炎、ウイルス性髄膜炎、手足口病、肝炎、筋肉炎、心筋炎、膵炎、流行性筋肉痛、脳炎、風邪、ヘルパンギナ、口蹄疫、喘息、毛細気管支炎、気管支炎、慢性閉塞性肺疾患、肺炎、縮膿症、中耳炎、単純ヘルペス、帯状ヘルペス、口内炎、及び水痘からなる群から選択される少なくとも1つであることを特徴とする、<7>に記載の薬学的組成物。
Claims (7)
- 下記化合物からなる群から選択される化合物、またはその薬学的に許容される塩:
及び
。 - 請求項1に記載の化合物またはその薬学的に許容される塩を含む、BET(Bromodomain Extra-Terminal)タンパク質関連疾患を予防または治療するための薬学的組成物。
- 前記BETタンパク質関連疾患が、癌と、自己免疫または炎症性疾患と、代謝性疾患と、ウイルス性疾患とからなる群から選択される少なくとも1つであることを特徴とする、請求項2に記載の薬学的組成物。
- 前記癌が、血液癌、多発性骨髄腫、急性骨髄性白血病、悪性リンパ腫、再生不良性貧血、胸腺癌、卵巣癌、子宮頸癌、乳癌、大腸癌、肝臓癌、胃癌、膵臓癌、結腸癌、腹膜転移癌、皮膚癌、膀胱癌、前立腺癌、甲状腺癌、肺癌、骨肉腫、線維性腫瘍、及び脳腫瘍からなる群から選択される少なくとも1つであることを特徴とする、請求項3に記載の薬学的組成物。
- 前記自己免疫または炎症性疾患が、慢性関節リウマチ、全身性エリテマトーデス、多発性硬化症、1型糖尿病、甲状腺機能亢進症、筋無力症、クローン病、強直性脊椎炎、乾癬、自己免疫性悪性貧血及びシェーグレン症候群、アレルギー、アレルギー性鼻炎、関節炎、喘息、慢性閉塞性肺疾患、変性関節疾患、皮膚炎、臓器拒絶、湿疹、肝炎、炎症性腸疾患、敗血症、敗血症症候群、敗血症ショック、及び非アルコール性脂肪肝炎からなる群から選択される少なくとも1つであることを特徴とする、請求項3に記載の薬学的組成物。
- 前記代謝性疾患が、高トリグリセリド血症、肥満、高脂血症、過インスリン血症、過血糖症、動脈硬化症、高血圧、2型糖尿病、及びインスリン抵抗性疾患からなる群から選択されるいずれか1つ以上である、請求項3に記載の薬学的組成物。
- 前記ウイルス性疾患が、ポリオ、急性出血性結膜炎、ウイルス性髄膜炎、手足口病、肝炎、筋肉炎、心筋炎、膵炎、流行性筋肉痛、脳炎、風邪、ヘルパンギナ、口蹄疫、喘息、毛細気管支炎、気管支炎、慢性閉塞性肺疾患、肺炎、縮膿症、中耳炎、単純ヘルペス、帯状ヘルペス、口内炎、及び水痘からなる群から選択される少なくとも1つであることを特徴とする、請求項3に記載の薬学的組成物。
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JP2012514631A (ja) | 2009-01-08 | 2012-06-28 | レスバーロジックス コーポレイション | 心血管疾患の予防および治療のための化合物 |
WO2013186612A1 (en) | 2012-04-19 | 2013-12-19 | Rvx Therapeutics Inc. | The use of substituted 2-phenyl-3h-quinazolin-4-ones and analogs for inhibiting bet (bromodomain and extra terminal domain) proteins |
US20180353462A1 (en) | 2015-05-02 | 2018-12-13 | Henry Lowe | Therapeutic agents containing cannabis flavonoid derivatives targeting kinases, sirtuins and oncogenic agents for the treatment of cancers |
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WO2006024545A1 (en) * | 2004-09-03 | 2006-03-09 | Stichting Voor De Technische Wetenschappen | Fused bicyclic natural compounds and their use as inhibitors of parp and parp-mediated inflammatory processes |
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US20230053152A1 (en) | 2023-02-16 |
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KR20210065882A (ko) | 2021-06-04 |
WO2021107656A3 (ko) | 2021-07-15 |
JP2023503201A (ja) | 2023-01-26 |
EP4067352A2 (en) | 2022-10-05 |
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KR102420262B1 (ko) | 2022-07-13 |
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