JP5508258B2 - トリアリール化合物および前記化合物を含む組成物 - Google Patents
トリアリール化合物および前記化合物を含む組成物 Download PDFInfo
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- JP5508258B2 JP5508258B2 JP2010510954A JP2010510954A JP5508258B2 JP 5508258 B2 JP5508258 B2 JP 5508258B2 JP 2010510954 A JP2010510954 A JP 2010510954A JP 2010510954 A JP2010510954 A JP 2010510954A JP 5508258 B2 JP5508258 B2 JP 5508258B2
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- heterocycloalkyl
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- 150000001875 compounds Chemical class 0.000 title claims description 128
- 239000000203 mixture Substances 0.000 title description 47
- 125000000217 alkyl group Chemical group 0.000 claims description 64
- 125000003118 aryl group Chemical group 0.000 claims description 44
- 125000003545 alkoxy group Chemical group 0.000 claims description 40
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 38
- 125000003342 alkenyl group Chemical group 0.000 claims description 31
- 125000000304 alkynyl group Chemical group 0.000 claims description 29
- 229910052736 halogen Inorganic materials 0.000 claims description 26
- 150000002367 halogens Chemical class 0.000 claims description 26
- 125000001072 heteroaryl group Chemical group 0.000 claims description 26
- 229910052739 hydrogen Inorganic materials 0.000 claims description 25
- 125000002877 alkyl aryl group Chemical group 0.000 claims description 23
- 239000001257 hydrogen Substances 0.000 claims description 23
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 23
- 125000003106 haloaryl group Chemical group 0.000 claims description 22
- 125000004663 dialkyl amino group Chemical group 0.000 claims description 20
- 150000002431 hydrogen Chemical class 0.000 claims description 20
- 125000004043 oxo group Chemical group O=* 0.000 claims description 13
- 125000005885 heterocycloalkylalkyl group Chemical group 0.000 claims description 12
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 6
- RWRDLPDLKQPQOW-UHFFFAOYSA-N tetrahydropyrrole Substances C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims 1
- -1 hydrate Chemical class 0.000 description 54
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 30
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 30
- 239000008194 pharmaceutical composition Substances 0.000 description 29
- 125000001188 haloalkyl group Chemical group 0.000 description 25
- 125000000753 cycloalkyl group Chemical group 0.000 description 22
- 239000003085 diluting agent Substances 0.000 description 22
- 150000003839 salts Chemical class 0.000 description 21
- 238000000034 method Methods 0.000 description 20
- 239000000243 solution Substances 0.000 description 20
- 239000004480 active ingredient Substances 0.000 description 18
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 17
- 229910052757 nitrogen Inorganic materials 0.000 description 17
- 150000001204 N-oxides Chemical class 0.000 description 16
- 229910052799 carbon Inorganic materials 0.000 description 16
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 16
- 239000007787 solid Substances 0.000 description 16
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 15
- 125000003282 alkyl amino group Chemical group 0.000 description 14
- 239000013078 crystal Substances 0.000 description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
- 239000003814 drug Substances 0.000 description 13
- 230000000694 effects Effects 0.000 description 13
- 125000005213 alkyl heteroaryl group Chemical group 0.000 description 12
- 125000001769 aryl amino group Chemical group 0.000 description 12
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 10
- 125000005119 alkyl cycloalkyl group Chemical group 0.000 description 10
- 201000010099 disease Diseases 0.000 description 10
- 229940079593 drug Drugs 0.000 description 10
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- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 9
- 125000005055 alkyl alkoxy group Chemical group 0.000 description 9
- 229910052785 arsenic Inorganic materials 0.000 description 9
- RQNWIZPPADIBDY-UHFFFAOYSA-N arsenic atom Chemical compound [As] RQNWIZPPADIBDY-UHFFFAOYSA-N 0.000 description 9
- 230000015572 biosynthetic process Effects 0.000 description 9
- 229910052732 germanium Inorganic materials 0.000 description 9
- GNPVGFCGXDBREM-UHFFFAOYSA-N germanium atom Chemical compound [Ge] GNPVGFCGXDBREM-UHFFFAOYSA-N 0.000 description 9
- 229910052698 phosphorus Inorganic materials 0.000 description 9
- 239000011574 phosphorus Substances 0.000 description 9
- 229910052710 silicon Inorganic materials 0.000 description 9
- 239000010703 silicon Substances 0.000 description 9
- 238000003786 synthesis reaction Methods 0.000 description 9
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
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- 239000007788 liquid Substances 0.000 description 8
- 239000003826 tablet Substances 0.000 description 8
- 125000003178 carboxy group Chemical class [H]OC(*)=O 0.000 description 7
- 239000003921 oil Substances 0.000 description 7
- 235000019198 oils Nutrition 0.000 description 7
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000013543 active substance Substances 0.000 description 6
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 6
- 239000000969 carrier Substances 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 6
- 239000003937 drug carrier Substances 0.000 description 6
- 150000002148 esters Chemical class 0.000 description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 6
- 229920006395 saturated elastomer Polymers 0.000 description 6
- 239000000725 suspension Substances 0.000 description 6
- 230000001225 therapeutic effect Effects 0.000 description 6
- 125000004001 thioalkyl group Chemical group 0.000 description 6
- BRPSWMCDEYMRPE-UHFFFAOYSA-N 4-[1,1-bis(4-hydroxyphenyl)ethyl]phenol Chemical compound C=1C=C(O)C=CC=1C(C=1C=CC(O)=CC=1)(C)C1=CC=C(O)C=C1 BRPSWMCDEYMRPE-UHFFFAOYSA-N 0.000 description 5
- 229920002261 Corn starch Polymers 0.000 description 5
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 5
- 125000005907 alkyl ester group Chemical group 0.000 description 5
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 5
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 5
- 239000002775 capsule Substances 0.000 description 5
- 239000008120 corn starch Substances 0.000 description 5
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- 239000000463 material Substances 0.000 description 5
- 102000039446 nucleic acids Human genes 0.000 description 5
- 108020004707 nucleic acids Proteins 0.000 description 5
- 150000007523 nucleic acids Chemical class 0.000 description 5
- 239000011780 sodium chloride Substances 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 5
- 239000003981 vehicle Substances 0.000 description 5
- 108020004414 DNA Proteins 0.000 description 4
- 102000053602 DNA Human genes 0.000 description 4
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 239000000654 additive Substances 0.000 description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 4
- 229910052794 bromium Inorganic materials 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 208000035475 disorder Diseases 0.000 description 4
- 238000001704 evaporation Methods 0.000 description 4
- 230000008020 evaporation Effects 0.000 description 4
- 150000004677 hydrates Chemical class 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 4
- 229910052760 oxygen Inorganic materials 0.000 description 4
- 239000001301 oxygen Substances 0.000 description 4
- 238000003752 polymerase chain reaction Methods 0.000 description 4
- 235000000346 sugar Nutrition 0.000 description 4
- 0 **(c(cc1*)cc(*)c1O*)(c(cc1*)cc(*)c1O*)c(cc1I)cc(*)c1O Chemical compound **(c(cc1*)cc(*)c1O*)(c(cc1*)cc(*)c1O*)c(cc1I)cc(*)c1O 0.000 description 3
- 125000001960 7 membered carbocyclic group Chemical group 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- 108010010803 Gelatin Proteins 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- 108091028043 Nucleic acid sequence Proteins 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 229930006000 Sucrose Natural products 0.000 description 3
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 3
- 230000009471 action Effects 0.000 description 3
- 125000003277 amino group Chemical group 0.000 description 3
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 3
- 125000004122 cyclic group Chemical group 0.000 description 3
- 239000008121 dextrose Substances 0.000 description 3
- 239000000839 emulsion Substances 0.000 description 3
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 3
- 125000002541 furyl group Chemical group 0.000 description 3
- 229920000159 gelatin Polymers 0.000 description 3
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- 235000019322 gelatine Nutrition 0.000 description 3
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- 238000001990 intravenous administration Methods 0.000 description 3
- 239000002502 liposome Substances 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 238000010369 molecular cloning Methods 0.000 description 3
- 239000008188 pellet Substances 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- 229920002477 rna polymer Polymers 0.000 description 3
- 239000003381 stabilizer Substances 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 239000005720 sucrose Substances 0.000 description 3
- 229910052717 sulfur Inorganic materials 0.000 description 3
- 239000011593 sulfur Substances 0.000 description 3
- 238000011282 treatment Methods 0.000 description 3
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 description 2
- FMPWRVUMYLGTRA-UHFFFAOYSA-N 1-[1,1-bis(4-methoxyphenyl)ethyl]-4-methoxybenzene Chemical compound C1=CC(OC)=CC=C1C(C)(C=1C=CC(OC)=CC=1)C1=CC=C(OC)C=C1 FMPWRVUMYLGTRA-UHFFFAOYSA-N 0.000 description 2
- XBQUOTRVJFIZGM-UHFFFAOYSA-N 4-[1,1-bis(3,5-diethoxy-4-hydroxyphenyl)ethyl]-2,6-diethoxyphenol Chemical compound CCOC1=C(O)C(OCC)=CC(C(C)(C=2C=C(OCC)C(O)=C(OCC)C=2)C=2C=C(OCC)C(O)=C(OCC)C=2)=C1 XBQUOTRVJFIZGM-UHFFFAOYSA-N 0.000 description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 2
- 241000167854 Bourreria succulenta Species 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
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- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
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Description
本発明は、新規なトリアリール化合物類、前記化合物を含む医薬組成物、及びその製造方法に関する。
核酸ポリメラーゼは酵素であり、その第1の作用は、新しい核酸、例えばデオキシリボ核酸(DNA)又はリボ核酸(RNA)を、存在する鋳型DNA又はRNAを用いて重合させることである。ポリメラーゼは、典型的に複製及び転写プロセスに含まれる。
一つの実施形態において本発明は、式Iの構造によって表される化合物、又はその異性体、塩、水和物、N−オキシド、結晶又はこれらの任意の組合せを提供する。
Zは、炭素、窒素、リン(phosphor)、ヒ素、ケイ素又はゲルマニウムであり;
R1、R2、R3、R4、R5及びR6は、独立に、アルキル(C2−C6)、アルケニル(C2−C6)、アルキニル(C2−C6)、アルコキシ(C2−C6)、アルキルアルコキシ、ハロアルキル、アルキルハロアルキル、アリール、アルキルアリール、ハロアリール、シクロアルキル、ヘテロシクロアルキル、アルキルシクロアルキル、アルキルへテロシクロアルキル、ヘテロアリール、アルキルへテロアリール、アミノ、モノアルキルアミノ、ジアルキルアミノ又はアリールアミノを含む同じ又は異なるものであり;及び
R7は、非存在、オキソ、水素、ヒドロキシ、ハロゲン、CN、NO2、アルキル(C1−C6)、アルケニル(C1−C6)、アルキニル(C1−C6)、アルコキシ(C1−C6)、ハロアルキル、アリール、アルキルアリール、ハロアリール、ヘテロシクロアルキル、アルキルへテロシクロアルキル、ヘテロアリール又はアルキルへテロアリールである。
Zは、炭素、窒素、リン、ヒ素、ケイ素又はゲルマニウムであり;
R’、R”及びR'”は、独立に、水素、アルキル、ハロアルキル、アルキルアミノ、アルキルエステル、フェニル、ベンジル、アルカニロイル、アセチル又はベンゾイルを含む同じ又は異なるものであり;
R1、R2、R3、R4、R5及びR6は、独立に、アルキル(C2−C6)、アルケニル(C2−C6)、アルキニル(C2−C6)、アルコキシ(C2−C6)、アルキルアルコキシ、ハロアルキル、アルキルハロアルキル、アリール、アルキルアリール、ハロアリール、シクロアルキル、ヘテロシクロアルキル、アルキルシクロアルキル、アルキルへテロシクロアルキル、ヘテロアリール、アルキルへテロアリール、アミノ、モノアルキルアミノ、ジアルキルアミノ又はアリールアミノを含む同じ又は異なるものであり;及び
R7は、非存在、オキソ、水素、ヒドロキシ、ハロゲン、CN、NO2、アルキル(C1−C6)、アルケニル(C1−C6)、アルキニル(C1−C6)、アルコキシ(C1−C6)、ハロアルキル、アリール、アルキルアリール、ハロアリール、ヘテロシクロアルキル、アルキルへテロシクロアルキル、ヘテロアリール又はアルキルへテロアリールである。
Xは炭素又は窒素であり;
R1は、非存在、アルコキシ、OCH2COOEt又はハロゲンであり;
R2及びR3は、独立に、水素、アルキル、アルコキシ、ヒドロキシル、又はOCH2COOAlkであり;及び
R4及びR5は、水素であるか、又は一緒になって飽和若しくは不飽和の5〜7員の炭素環(carbocyclic ring)を形成する。
Zは、炭素、窒素、リン、ヒ素、ケイ素又はゲルマニウムであり;
R1、R2、R3、R4、R5及びR6は、独立に、アルキル(C2−C6)、アルケニル(C2−C6)、アルキニル(C2−C6)、アルコキシ(C2−C6)、アルキルアルコキシ、ハロアルキル、アルキルハロアルキル、アリール、アルキルアリール、ハロアリール、シクロアルキル、ヘテロシクロアルキル、アルキルシクロアルキル、アルキルへテロシクロアルキル、ヘテロアリール、アルキルへテロアリール、アミノ、モノアルキルアミノ、ジアルキルアミノ又はアリールアミノを含む同じ又は異なるものであり;及び
R7は、非存在、オキソ、水素、ヒドロキシ、ハロゲン、CN、NO2、アルキル(C1−C6)、アルケニル(C1−C6)、アルキニル(C1−C6)、アルコキシ(C1−C6)、ハロアルキル、アリール、アルキルアリール、ハロアリール、ヘテロシクロアルキル、アルキルへテロシクロアルキル、ヘテロアリール又はアルキルへテロアリールである。
Zは、炭素、窒素、リン、ヒ素、ケイ素又はゲルマニウムであり;
R’、R”及びR'”は、独立に、水素、アルキル、ハロアルキル、アルキルアミノ、アルキルエステル、フェニル、ベンジル、アルカニロイル、アセチル又はベンゾイルを含む同じ又は異なるものであり;
R1、R2、R3、R4、R5及びR6は、独立に、アルキル(C2−C6)、アルケニル(C2−C6)、アルキニル(C2−C6)、アルコキシ(C2−C6)、アルキルアルコキシ、ハロアルキル、アルキルハロアルキル、アリール、アルキルアリール、ハロアリール、シクロアルキル、ヘテロシクロアルキル、アルキルシクロアルキル、アルキルへテロシクロアルキル、ヘテロアリール、アルキルへテロアリール、アミノ、モノアルキルアミノ、ジアルキルアミノ又はアリールアミノを含む同じ又は異なるものであり;及び
R7は、非存在、オキソ、水素、ヒドロキシ、ハロゲン、CN、NO2、アルキル(C1−C6)、アルケニル(C1−C6)、アルキニル(C1−C6)、アルコキシ(C1−C6)、ハロアルキル、アリール、アルキルアリール、ハロアリール、ヘテロシクロアルキル、アルキルへテロシクロアルキル、ヘテロアリール又はアルキルへテロアリールである。
Xは炭素又は窒素であり;
R1は、非存在、アルコキシ、OCH2COOEt又はハロゲンであり;
R2及びR3は、独立に、水素、アルキル、アルコキシ、ヒドロキシル、又はOCH2COOAlkであり;及び
R4及びR5は、水素であるか、又は一緒になって飽和若しくは不飽和の5〜7員の炭素環を形成する。
以下の詳細な説明で本発明の充分な理解をもたらすために、数多くの具体的な詳細が示されている。しかしこれらの具体的な詳細無しでも本発明が実施できることは、当業者に理解されるであろう。他の例では、本発明をぼやけさせないようにするため、周知の方法、手順、及び成分は詳細に記載されていない。
Zは、炭素、窒素、リン、ヒ素、ケイ素又はゲルマニウムであり;
R1、R2、R3、R4、R5及びR6は、独立に、アルキル(C2−C6)、アルケニル(C2−C6)、アルキニル(C2−C6)、アルコキシ(C2−C6)、アルキルアルコキシ、ハロアルキル、アルキルハロアルキル、アリール、アルキルアリール、ハロアリール、シクロアルキル、ヘテロシクロアルキル、アルキルシクロアルキル、アルキルへテロシクロアルキル、ヘテロアリール、アルキルへテロアリール、アミノ、モノアルキルアミノ、ジアルキルアミノ又はアリールアミノを含む同じ又は異なるものであり;及び
R7は、非存在、オキソ、水素、ヒドロキシ、ハロゲン、CN、NO2、アルキル(C1−C6)、アルケニル(C1−C6)、アルキニル(C1−C6)、アルコキシ(C1−C6)、ハロアルキル、アリール、アルキルアリール、ハロアリール、ヘテロシクロアルキル、アルキルへテロシクロアルキル、ヘテロアリール又はアルキルへテロアリールである。
Zは、炭素、窒素、リン、ヒ素、ケイ素又はゲルマニウムであり;
R’、R”及びR'”は、独立に、水素、アルキル、ハロアルキル、アルキルアミノ、アルキルエステル、フェニル、ベンジル、アルカニロイル、アセチル又はベンゾイルを含む同じ又は異なるものであり;
R1、R2、R3、R4、R5及びR6は、独立に、アルキル(C2−C6)、アルケニル(C2−C6)、アルキニル(C2−C6)、アルコキシ(C2−C6)、アルキルアルコキシ、ハロアルキル、アルキルハロアルキル、アリール、アルキルアリール、ハロアリール、シクロアルキル、ヘテロシクロアルキル、アルキルシクロアルキル、アルキルへテロシクロアルキル、ヘテロアリール、アルキルへテロアリール、アミノ、モノアルキルアミノ、ジアルキルアミノ又はアリールアミノを含む同じ又は異なるものであり;及び
R7は、非存在、オキソ、水素、ヒドロキシ、ハロゲン、CN、NO2、アルキル(C1−C6)、アルケニル(C1−C6)、アルキニル(C1−C6)、アルコキシ(C1−C6)、ハロアルキル、アリール、アルキルアリール、ハロアリール、ヘテロシクロアルキル、アルキルへテロシクロアルキル、ヘテロアリール又はアルキルへテロアリールである。
R’、R”及びR'”は、独立に、水素、アルキル、ハロアルキル、フェニル、アルキルエステル、ベンジル、アルカニロイル、アセチル又はベンゾイルを含む同じ又は異なるものであり;
R1’、R2’、R3’、R4’、R5’及びR6’は、ハロゲン、アリール、アルキル、シクロアルキル、ヘテロシクロアルキル、アルコキシ(C2−C6)、アミノ、モノアルキルアミノ、ジアルキルアミノ又はアリールアミノ基を含む同じ又は異なるものであり;及び
R7は、オキソ、水素、ヒドロキシ、ハロゲン、CN、NO2、アルキル(C1−C6)、アルケニル(C1−C6)、アルキニル(C1−C6)、アルコキシ(C1−C6)、ハロアルキル、アリール、アルキルアリール、ハロアリール、ヘテロシクロアルキル、アルキルへテロシクロアルキル、ヘテロアリール又はアルキルへテロアリールである。
Zは、炭素、窒素、リン、ヒ素、ケイ素又はゲルマニウムであり;
R8からR16は、同じ又は異なって、H、D、OH、ハロゲン、ニトロ、CN、ニトリルアミド、アミドスルフィド、アミノ、アルデヒド、置換ケトン、−COOH、エステル、トリフルオロメチル、アミド、置換又は未置換アルキル、アルケニル、アルキニル、アリール、アリールアルキル、アルキルアリール、アリールスルホニル、アリールアルキレンスルホニル、アルコキシ、ハロアルキル、ハロアリール、アリールオキシ、アミノ、モノアルキルアミノ、ジアルキルアミノ、アルキルアミド、アリールアミノ、アリールアミド、アルキルチオ、アリールチオ、ヘテロシクロアルキル、アルキルヘテロシクロアルキル、ヘテロシクロアルキルアルキル、ヘテロアリール、ヘテロアリールアルキル、アルキルヘテロアリールであるか、又はR10、R11若しくはR14は、主の芳香環と共に、縮合シクロアルキル、ヘテロシクロアルキル、芳香環若しくは芳香族複素環を形成し;及び
R17は、H、D、OH、ハロゲン、オキソ、ニトロ、CN、ニトリルアミド、アミドスルフィド、アミノ、アルデヒド、置換ケトン、−COOH、エステル、トリフルオロメチル、アミド、置換又は未置換アルキル、アルケニル、アルキニル、アリール、アリールアルキル、アルキルアリール、アリールスルホニル、アリールアルキレンスルホニル、アルコキシ、ハロアルキル、ハロアリール、アリールオキシ、モノアルキルアミノ、ジアルキルアミノ、アルキルアミド、アリールアミノ、アリールアミド、アルキルチオ、アリールチオ、ヘテロシクロアルキル、アルキルヘテロシクロアルキル、ヘテロシクロアルキルアルキル、ヘテロアリール、ヘテロアリールアルキル、アルキルヘテロアリールである。
Xは炭素又は窒素であり;
R1は、非存在、アルコキシ、OCH2COOEt又はハロゲンであり;
R2及びR3は、独立に、水素、アルキル、アルコキシ、ヒドロキシル、又はOCH2COOAlkであり;及び
R4及びR5は、水素であるか、又は一緒になって飽和若しくは不飽和の5〜7員の炭素環を形成する。
Zは、炭素、窒素、リン、ヒ素、ケイ素又はゲルマニウムであり;
R1、R2、R3、R4、R5及びR6は、独立に、アルキル(C2−C6)、アルケニル(C1−C6)、アルキニル(C1−C6)、アルコキシ(C2−C6)、アルキルアルコキシ、ハロアルキル、アルキルハロアルキル、アリール、アルキルアリール、ハロアリール、シクロアルキル、ヘテロシクロアルキル、アルキルシクロアルキル、アルキルへテロシクロアルキル、ヘテロアリール、アルキルへテロアリール、アミノ、モノアルキルアミノ、ジアルキルアミノ又はアリールアミノを含む同じ又は異なるものであり;及び
R7は、非存在、オキソ、水素、ヒドロキシ、ハロゲン、CN、NO2、アルキル(C1−C6)、アルケニル(C1−C6)、アルキニル(C1−C6)、アルコキシ(C1−C6)、ハロアルキル、アリール、アルキルアリール、ハロアリール、ヘテロシクロアルキル、アルキルへテロシクロアルキル、ヘテロアリール又はアルキルへテロアリールである。
Zは、炭素、窒素、リン、ヒ素、ケイ素又はゲルマニウムであり;
R’、R”及びR'”は、独立に、水素、アルキル、ハロアルキル、アルキルアミノ、アルキルエステル、フェニル、ベンジル、アルカニロイル、アセチル又はベンゾイルを含む同じ又は異なるものであり;
R1、R2、R3、R4、R5及びR6は、独立に、アルキル(C2−C6)、アルケニル(C2−C6)、アルキニル(C2−C6)、アルコキシ(C2−C6)、アルキルアルコキシ、ハロアルキル、アルキルハロアルキル、アリール、アルキルアリール、ハロアリール、シクロアルキル、ヘテロシクロアルキル、アルキルシクロアルキル、アルキルへテロシクロアルキル、ヘテロアリール、アルキルへテロアリール、アミノ、モノアルキルアミノ、ジアルキルアミノ又はアリールアミノを含む同じ又は異なるものであり;及び
R7は、非存在、オキソ、水素、ヒドロキシ、ハロゲン、CN、NO2、アルキル(C1−C6)、アルケニル(C1−C6)、アルキニル(C1−C6)、アルコキシ(C1−C6)、ハロアルキル、アリール、アルキルアリール、ハロアリール、ヘテロシクロアルキル、アルキルへテロシクロアルキル、ヘテロアリール又はアルキルへテロアリールである。
式VIの化合物の合成
1,1,1−トリス(4−ヒドロキシフェニル)エタン(4g、13mM)、ホルムアルデヒド(3.6g、120mM)及び40%のジメチルアミン水溶液(15mL)を、50mLの水及び60mLのEtOHの溶液に添加した。溶液を2.5時間還流した。溶媒の部分蒸発で白色固体を沈殿させ、これをろ過し、水で洗浄し、乾燥して、式VIの化合物の白色固体7.85gを得た(収率93%、mp.=169°)。
式VIIの化合物の合成
式VIIの化合物を、実施例1に記載の方法と類似する方法によって合成した。
式VIIIの化合物の合成
20mLの水及び25mLのEtOH中の1,1,1−トリス(4−ヒドロキシフェニル)エタン(1.53g、5mM)、ホルムアルデヒド(1.35g、45mM)及び1−メチルピペラジン(2.5mL、50mM)を3時間還流した。蒸発で固体を得た。この固体は、TLC及びNMRによれば二つの生成物を含有し、これは出発物質ではなかった。ホルムアルデヒド(0.75g、25mM)及び1−メチルピペラジン(1.5mL、30mM)を、5mLの水及び10mLのEtOHに添加し、反応を4時間還流した。蒸発及び後処理(workup)で、3.3gの淡黄色乃至白色の固体を得た(収率67%、mp.−63°)。エタノールに可溶、及び水への溶解度は非常に良好。
式IXの化合物の合成
式IXの化合物を、実施例1に記載の方法と類似する方法によって合成した。白色固体が得られた。mp.=178°。
式Xの化合物の合成
式Xの化合物を、実施例1に記載の方法と類似する方法によって合成した。白色固体が得られた。mp.=135°。
式XIの化合物の合成
式XIの化合物を、実施例1に記載の方法と類似する方法によって合成した。白色固体が得られた。mp.=212°。
1,1,1−トリス(4−ヒドロキシ−3,5−ジエトキシ−フェニル)−エタンの合成
工程1:実施例1に記載の方法と類似する方法によって製造した式IVの化合物(2.98g、4.6mM)を20mLの無水酢酸に添加し、100°に4時間加熱した。混合物を冷却し、水を添加した。混合物を室温で一晩撹拌し、次いでCH2Cl2で抽出した。溶媒を蒸発させて、黄色油としてノナ−アセテート誘導体を得て、これをさらにクロマトグラフィー(シリカゲル;1%MeOH/CH2Cl2)で精製して、3.2gの粘性黄色油を得た(収率80%)。
1,1,1−トリス(4−ヒドロキシ−3,5−ジブロモ−フェニル)−エタンの合成
工程1:水10mL中のNaOH(1g、25mM)、及び硫酸ジメチル(5.1g、40mM)(モル比1:8)の溶液を、1時間かけて同時に少量ずつ、エタノール20mL及び水10mL中の1,1,1−トリス(4−ヒドロキシフェニル)−エタン(1.53g、5mM)の溶液に添加した。次いで溶液を1時間還流し、室温で70時間撹拌した。白色沈殿物をろ過し、水で洗浄し、乾燥して、1.74gの1,1,1−トリス(4−メトキシフェニル)−エタンを得た。50mLのエタノールからの2回の再結晶で、1.15gの白色結晶を得た(収率66%、mp.−160°)。CH2Cl2中のTLC Rf=0.85。
1,1,1−トリス(4−ヒドロキシ−3,5−ジヨード−フェニル)−エタン(化合物XIV)の合成
エタノール40mL及び水40mL中の氷冷した1,1,1−トリス(4−ヒドロキシフェニル)−エタン(1.53g、5mM)に、KOH(2.2g、39.2mM)、これに続けてKI(5.8g、34.8mM)及びヨウ素(8.8g、34.7mM)を添加した。色が紫色から茶色に変化する。反応を室温で3時間撹拌した。混合物を砕いた氷に添加した。酸性pHにするために濃HClを添加し、チオスルフェート溶液で処理し、ジクロロメタンで抽出した。蒸発で5.1gの淡褐色固体であるヘキサヨード生成物を得て、これに続けてエタノール中での粉砕によって3gの白色固体を得た(収率61%、mp=230°)。RF=0.8(5%MeOH−CH2Cl2中)。
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