CN110035753B - 1-苯基丙酮化合物及其用途 - Google Patents
1-苯基丙酮化合物及其用途 Download PDFInfo
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- CN110035753B CN110035753B CN201780075159.1A CN201780075159A CN110035753B CN 110035753 B CN110035753 B CN 110035753B CN 201780075159 A CN201780075159 A CN 201780075159A CN 110035753 B CN110035753 B CN 110035753B
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- Prior art keywords
- compound
- phenyl
- propan
- methylpiperazin
- morpholinopropan
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- -1 1-phenyl acetonide Chemical compound 0.000 title claims abstract description 85
- 150000001875 compounds Chemical class 0.000 claims abstract description 169
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 27
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims abstract description 23
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims abstract description 22
- 229910052711 selenium Inorganic materials 0.000 claims abstract description 22
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 19
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 claims abstract description 18
- 208000026310 Breast neoplasm Diseases 0.000 claims abstract description 17
- 206010006187 Breast cancer Diseases 0.000 claims abstract description 16
- 125000001424 substituent group Chemical group 0.000 claims abstract description 15
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 14
- 206010029260 Neuroblastoma Diseases 0.000 claims abstract description 13
- 239000002246 antineoplastic agent Substances 0.000 claims abstract description 13
- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 claims abstract description 9
- 208000032852 chronic lymphocytic leukemia Diseases 0.000 claims abstract description 9
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 50
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 claims description 25
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 claims description 25
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 claims description 25
- OJBZYLXALQSOCF-UHFFFAOYSA-N 1-(4-heptylphenyl)-3-(4-methylpiperazin-1-yl)propan-1-one Chemical compound C(CCCCCC)C1=CC=C(C=C1)C(CCN1CCN(CC1)C)=O OJBZYLXALQSOCF-UHFFFAOYSA-N 0.000 claims description 25
- NZVIPIOEHZCUPC-UHFFFAOYSA-N 1-(4-heptylphenyl)-3-morpholin-4-ylpropan-1-one Chemical compound C(CCCCCC)C1=CC=C(C=C1)C(CCN1CCOCC1)=O NZVIPIOEHZCUPC-UHFFFAOYSA-N 0.000 claims description 25
- OXJWQNHWZFNERF-UHFFFAOYSA-N 1-(4-heptylselanylphenyl)-3-morpholin-4-ylpropan-1-one Chemical compound C(CCCCCC)[Se]C1=CC=C(C=C1)C(CCN1CCOCC1)=O OXJWQNHWZFNERF-UHFFFAOYSA-N 0.000 claims description 25
- SHNQCTQKJYTOTL-UHFFFAOYSA-N 1-(4-heptylsulfanylphenyl)-3-(4-methylpiperazin-1-yl)propan-1-one Chemical compound C(CCCCCC)SC1=CC=C(C=C1)C(CCN1CCN(CC1)C)=O SHNQCTQKJYTOTL-UHFFFAOYSA-N 0.000 claims description 25
- NIFWAIYELZWMOM-UHFFFAOYSA-N 1-(4-heptylsulfanylphenyl)-3-morpholin-4-ylpropan-1-one Chemical compound C(CCCCCC)SC1=CC=C(C=C1)C(CCN1CCOCC1)=O NIFWAIYELZWMOM-UHFFFAOYSA-N 0.000 claims description 25
- IKVQHWQLXZLIDS-UHFFFAOYSA-N 1-(4-heptylsulfanylphenyl)-3-piperidin-1-ylpropan-1-one Chemical compound C(CCCCCC)SC1=CC=C(C=C1)C(CCN1CCCCC1)=O IKVQHWQLXZLIDS-UHFFFAOYSA-N 0.000 claims description 25
- JWTFTGVGPNLKIM-UHFFFAOYSA-N 1-(4-hexylsulfanylphenyl)-3-(4-methylpiperazin-1-yl)propan-1-one Chemical compound C(CCCCC)SC1=CC=C(C=C1)C(CCN1CCN(CC1)C)=O JWTFTGVGPNLKIM-UHFFFAOYSA-N 0.000 claims description 25
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 claims description 25
- YSUIQYOGTINQIN-UZFYAQMZSA-N 2-amino-9-[(1S,6R,8R,9S,10R,15R,17R,18R)-8-(6-aminopurin-9-yl)-9,18-difluoro-3,12-dihydroxy-3,12-bis(sulfanylidene)-2,4,7,11,13,16-hexaoxa-3lambda5,12lambda5-diphosphatricyclo[13.2.1.06,10]octadecan-17-yl]-1H-purin-6-one Chemical compound NC1=NC2=C(N=CN2[C@@H]2O[C@@H]3COP(S)(=O)O[C@@H]4[C@@H](COP(S)(=O)O[C@@H]2[C@@H]3F)O[C@H]([C@H]4F)N2C=NC3=C2N=CN=C3N)C(=O)N1 YSUIQYOGTINQIN-UZFYAQMZSA-N 0.000 claims description 25
- 229940126657 Compound 17 Drugs 0.000 claims description 25
- XRWSZZJLZRKHHD-WVWIJVSJSA-N asunaprevir Chemical compound O=C([C@@H]1C[C@H](CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)OC1=NC=C(C2=CC=C(Cl)C=C21)OC)N[C@]1(C(=O)NS(=O)(=O)C2CC2)C[C@H]1C=C XRWSZZJLZRKHHD-WVWIJVSJSA-N 0.000 claims description 25
- 229940126543 compound 14 Drugs 0.000 claims description 25
- 229940125961 compound 24 Drugs 0.000 claims description 25
- NLIRCCPCCRFQQB-UHFFFAOYSA-N 1-(4-heptoxyphenyl)-3-(4-methylpiperazin-1-yl)propan-1-one Chemical compound C(CCCCCC)OC1=CC=C(C=C1)C(CCN1CCN(CC1)C)=O NLIRCCPCCRFQQB-UHFFFAOYSA-N 0.000 claims description 21
- DYKACALDGQXIQC-UHFFFAOYSA-N 1-(4-heptylselanylphenyl)-3-(4-methylpiperazin-1-yl)propan-1-one Chemical compound C(CCCCCC)[Se]C1=CC=C(C=C1)C(CCN1CCN(CC1)C)=O DYKACALDGQXIQC-UHFFFAOYSA-N 0.000 claims description 21
- PJQKKHOHAOAJKV-UHFFFAOYSA-N 1-(4-heptylselanylphenyl)-3-piperidin-1-ylpropan-1-one Chemical compound C(CCCCCC)[Se]C1=CC=C(C=C1)C(CCN1CCCCC1)=O PJQKKHOHAOAJKV-UHFFFAOYSA-N 0.000 claims description 21
- RYSHHRGWRYZJMC-UHFFFAOYSA-N 1-(4-pentylsulfanylphenyl)-3-piperidin-1-ylpropan-1-one Chemical compound C(CCCC)SC1=CC=C(C=C1)C(CCN1CCCCC1)=O RYSHHRGWRYZJMC-UHFFFAOYSA-N 0.000 claims description 21
- KGNDCEVUMONOKF-UGPLYTSKSA-N benzyl n-[(2r)-1-[(2s,4r)-2-[[(2s)-6-amino-1-(1,3-benzoxazol-2-yl)-1,1-dihydroxyhexan-2-yl]carbamoyl]-4-[(4-methylphenyl)methoxy]pyrrolidin-1-yl]-1-oxo-4-phenylbutan-2-yl]carbamate Chemical compound C1=CC(C)=CC=C1CO[C@H]1CN(C(=O)[C@@H](CCC=2C=CC=CC=2)NC(=O)OCC=2C=CC=CC=2)[C@H](C(=O)N[C@@H](CCCCN)C(O)(O)C=2OC3=CC=CC=C3N=2)C1 KGNDCEVUMONOKF-UGPLYTSKSA-N 0.000 claims description 21
- 229940125810 compound 20 Drugs 0.000 claims description 21
- 229940125833 compound 23 Drugs 0.000 claims description 21
- 229940125898 compound 5 Drugs 0.000 claims description 21
- JAXFJECJQZDFJS-XHEPKHHKSA-N gtpl8555 Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)N[C@H](B1O[C@@]2(C)[C@H]3C[C@H](C3(C)C)C[C@H]2O1)CCC1=CC=C(F)C=C1 JAXFJECJQZDFJS-XHEPKHHKSA-N 0.000 claims description 21
- GLKNBGOKXZJIAF-UHFFFAOYSA-N 1-(4-hexylsulfanylphenyl)-3-morpholin-4-ylpropan-1-one Chemical compound C(CCCCC)SC1=CC=C(C=C1)C(CCN1CCOCC1)=O GLKNBGOKXZJIAF-UHFFFAOYSA-N 0.000 claims description 19
- 239000003814 drug Substances 0.000 claims description 19
- UFUASNAHBMBJIX-UHFFFAOYSA-N propan-1-one Chemical compound CC[C]=O UFUASNAHBMBJIX-UHFFFAOYSA-N 0.000 claims description 18
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims description 16
- TYZVDSJPWONVCP-UHFFFAOYSA-N 1-(4-heptylphenyl)-3-piperidin-1-ylpropan-1-one Chemical compound C1=CC(CCCCCCC)=CC=C1C(=O)CCN1CCCCC1 TYZVDSJPWONVCP-UHFFFAOYSA-N 0.000 claims description 13
- SPPTXAJILJYJLY-UHFFFAOYSA-N 1-(4-hexylsulfanylphenyl)-3-piperidin-1-ylpropan-1-one Chemical compound C(CCCCC)SC1=CC=C(C=C1)C(CCN1CCCCC1)=O SPPTXAJILJYJLY-UHFFFAOYSA-N 0.000 claims description 13
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 claims description 13
- QBWKPGNFQQJGFY-QLFBSQMISA-N 3-[(1r)-1-[(2r,6s)-2,6-dimethylmorpholin-4-yl]ethyl]-n-[6-methyl-3-(1h-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl]-1,2-thiazol-5-amine Chemical compound N1([C@H](C)C2=NSC(NC=3C4=NC=C(N4C=C(C)N=3)C3=CNN=C3)=C2)C[C@H](C)O[C@H](C)C1 QBWKPGNFQQJGFY-QLFBSQMISA-N 0.000 claims description 13
- 229940125773 compound 10 Drugs 0.000 claims description 13
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- 229940125846 compound 25 Drugs 0.000 claims description 13
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 claims description 13
- 125000002252 acyl group Chemical group 0.000 claims description 12
- 238000006467 substitution reaction Methods 0.000 claims description 12
- GLGNXYJARSMNGJ-VKTIVEEGSA-N (1s,2s,3r,4r)-3-[[5-chloro-2-[(1-ethyl-6-methoxy-2-oxo-4,5-dihydro-3h-1-benzazepin-7-yl)amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound CCN1C(=O)CCCC2=C(OC)C(NC=3N=C(C(=CN=3)Cl)N[C@H]3[C@H]([C@@]4([H])C[C@@]3(C=C4)[H])C(N)=O)=CC=C21 GLGNXYJARSMNGJ-VKTIVEEGSA-N 0.000 claims description 9
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 claims description 9
- MGBSEAVFZLXRPF-UHFFFAOYSA-N 1-(4-heptoxyphenyl)-3-piperidin-1-ylpropan-1-one Chemical compound C1=CC(OCCCCCCC)=CC=C1C(=O)CCN1CCCCC1 MGBSEAVFZLXRPF-UHFFFAOYSA-N 0.000 claims description 9
- YFNJVZDFFGTZIR-UHFFFAOYSA-N 3-(4-methylpiperazin-1-yl)-1-(4-pentylsulfanylphenyl)propan-1-one Chemical compound CN1CCN(CC1)CCC(=O)C1=CC=C(C=C1)SCCCCC YFNJVZDFFGTZIR-UHFFFAOYSA-N 0.000 claims description 9
- KAYLAACFSGZSCT-UHFFFAOYSA-N 3-morpholin-4-yl-1-(4-pentylsulfanylphenyl)propan-1-one Chemical compound O1CCN(CC1)CCC(=O)C1=CC=C(C=C1)SCCCCC KAYLAACFSGZSCT-UHFFFAOYSA-N 0.000 claims description 9
- 125000004195 4-methylpiperazin-1-yl group Chemical group [H]C([H])([H])N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 claims description 9
- OPFJDXRVMFKJJO-ZHHKINOHSA-N N-{[3-(2-benzamido-4-methyl-1,3-thiazol-5-yl)-pyrazol-5-yl]carbonyl}-G-dR-G-dD-dD-dD-NH2 Chemical compound S1C(C=2NN=C(C=2)C(=O)NCC(=O)N[C@H](CCCN=C(N)N)C(=O)NCC(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(N)=O)=C(C)N=C1NC(=O)C1=CC=CC=C1 OPFJDXRVMFKJJO-ZHHKINOHSA-N 0.000 claims description 9
- QCCDLTOVEPVEJK-UHFFFAOYSA-N benzyl methyl ketone Natural products CC(=O)CC1=CC=CC=C1 QCCDLTOVEPVEJK-UHFFFAOYSA-N 0.000 claims description 9
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- 239000008194 pharmaceutical composition Substances 0.000 claims description 8
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- VJZCZCUEZMGVCL-UHFFFAOYSA-N 1-(4-hexoxyphenyl)-3-morpholin-4-ylpropan-1-one Chemical compound C1=CC(OCCCCCC)=CC=C1C(=O)CCN1CCOCC1 VJZCZCUEZMGVCL-UHFFFAOYSA-N 0.000 claims description 7
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- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 claims description 5
- WXYWMSOSIIBMMM-UHFFFAOYSA-N 1-(4-hexoxyphenyl)-3-piperidin-1-ylpropan-1-one Chemical compound C1=CC(OCCCCCC)=CC=C1C(=O)CCN1CCCCC1 WXYWMSOSIIBMMM-UHFFFAOYSA-N 0.000 claims description 5
- LNUFLCYMSVYYNW-ZPJMAFJPSA-N [(2r,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[[(3s,5s,8r,9s,10s,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl]oxy]-4,5-disulfo Chemical compound O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)[C@H]1O[C@H](COS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@H](OS(O)(=O)=O)[C@H]1OS(O)(=O)=O LNUFLCYMSVYYNW-ZPJMAFJPSA-N 0.000 claims description 5
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Abstract
Description
描述
发明领域
本发明涉及有效诱导受慢性淋巴性白血病影响的患者的恶性B细胞的细胞凋亡和在体外诱导几种肿瘤类型的其他细胞模型的恶性B细胞的细胞凋亡的1-苯基丙酮化合物。
现有技术
具有以下报道的式的FTY720(也称为芬戈莫德(fingolimod),并且由Novartis以GilenyaTM销售),即2-氨基-2[2-(4-辛基苯基)乙基]-1,3-丙二醇盐酸盐,
是鞘氨醇的结构类似物,通过修饰天然化合物合成,该天然化合物具有免疫抑制作用,称为多球壳菌素,别名ISP-1,是昆虫致病性真菌Isaria sinclairii的代谢物(Fujita T等人,J Antibiot.,1994,47:208-15)。具有强大的免疫抑制活性的后者已经被用作开发具有更小的副作用的更有效的免疫抑制剂的先导化合物[Adachi等人,Bioorg.Med.Chem.Lett.1995;5:853-56;Adachi K.,Chiba K.,Perspect Medicin Chem2008;1:11-23.2]。FTY720最初就其本身或与经典免疫抑制剂联合作为预防移植后排斥的潜在药物被测试,所述经典免疫抑制剂诸如环孢菌素[Chiba K.等人,TransplantProc.1996,28(2):1056-1059;Brinkmann等人,J Biol Chem.2002,277(24):21453-21457],但在该领域没有显示出超越环孢菌素的优势,将兴趣指向对淋巴细胞向次级淋巴器官迁移的抑制作用,从而开辟了治疗免疫紊乱(诸如多发性硬化)的新的可能的机会[Mansoor M.,Melendez A.J.,Rev Recent Clin Trials.2008,3(1):62-69]。FTY720分别于2010年和2011年被美国FDA和欧洲的欧洲药品管理局批准用于治疗多发性硬化,特别是复发-缓解型多发性硬化。
FTY720的免疫抑制活性与其在淋巴细胞中被酶,鞘氨醇激酶2(SphK2)转化为磷酸化形式(FTY720-P)有关,鞘氨醇激酶2(SphK2)识别该药物,因为该药物在结构上与天然底物鞘氨醇相似。随后,FTY720-P从细胞中挤出(extruded),并且它与G蛋白偶联的鞘氨醇-1-磷酸(S1P)受体(特别是被称为S1P1的受体)相互作用,导致受体内化和降解。在缺乏这些受体的情况下,不再能够与天然配体S1P相互作用的淋巴细胞被隔离在次级淋巴器官中,导致全身循环淋巴细胞减少症(lymphopenia)[Brinkmann等人,Nat Rev Drug Discov.2010Nov,9(11):883-9;和专利申请WO 2007/143081 A2]。在旨在探索FTY720诱导的淋巴细胞减少症的研究期间,观察到该剂诱导的外周淋巴细胞的细胞凋亡[Nagahara等人,Immunopharmacology 2000,48:75-85;Nagahara等人,J Immunol 2000,165:3250-3259;Fufino M.,Li X.K.,Kitazawa Y.等人,J Pharmacol Exp Thar 2002,300:939-45],并且这引导了对其作为抗肿瘤剂的潜力的评估[Pinschewer D.D.,Brinkmann V.,Mender D.,Neurology 2011,76:515-9]。因此,证明了FTY720能够诱导来源于血液[Liu等人,Blood2008,111:275-84;Neviani等人,J Cin Invest 2007,117:2408-21]和实体赘生物(solidneoplasm)二者的细胞的细胞凋亡,所述实体赘生物诸如前列腺、膀胱、肾、胰腺、肝、乳腺、结肠、胃和肺赘生物[Permpongkosol等人,Int J Cancer 2002,98:167sfingo-72;Azuma等人,J Urol 2003,169:2372-7;Ubel等人,Anticancer Res 2007,27:75-88;Shen等人,Cancer Lett 2007,254:288-97;Ho等人,Mol Cancer Thor 2005,4:1430-8;Azuma等人,Cancer Res 2002,62:1410-9;Nagaoka等人,Bid Pharm 2008,31:117741;Meng等人,JCell Biochem 2010,111:218-28;Salinas等人,Int Immunopharmacol 2009,9:689-93])。关于细胞死亡潜在的分子机制,胱天蛋白酶依赖性细胞凋亡途径已经受到了质疑,其中涉及胱天蛋白酶9和3[Zheng等人,sfingo J Cell Biochem 111:218-228,2010],有时与促凋亡蛋白Bad、Bax、Bid和Btf的表达增加[Ubai等人,Anticancer Res 27:75-88,2007],以及非胱天蛋白酶依赖性细胞凋亡途径有关,在非胱天蛋白酶依赖性细胞凋亡途径中,取决于细胞类型,蛋白激酶,诸如Akt[Liu等人,Clin Cancer Res 16:3182-3192,2010]和ERK1/2[Liu等人,Blood 111:275-284;200824]的活化状态、活性氧物质的生成[Wallington-Beddoe等人,Autophagy 7:707-715,2011]和自噬诱导[Liu等人,Clin Cancer Res 16:3182-3192,2010;Liu等人,Blood 111:275-284,2008]、以及自噬[Zhang N.等人,Autophagy 6:1157-1167,2010;Wallington-Beddoe等人,Autophagy 7:707-715,2011;Liao等人,Eur J Pharm Sci 45:600-605,2012]起了作用。需要注意的是,FTY720在肿瘤细胞中诱导细胞死亡的能力不依赖于药物磷酸化,并且因此不依赖于免疫抑制机制[Wallington-Beddoe等人,Autophagy 7:707-715,2011]。尽管事实上FTY720介导细胞死亡的机制尚未被完全阐明,但已提出非磷酸化形式的FTY720的分子靶来解释该生物学效应。虽然一方面,活性氧物质在FTY720诱导的急性淋巴细胞白血病[Wallington-Beddoe等人,Autophagy 7:707-715,2011]、套细胞淋巴瘤(mantle lymphoma)[Liu等人,Clin CancerRes 16:3182-3192,2010]和多发性骨髓瘤[Liao等人,Eur J Pharm Sci 45:600-605,2012]中细胞死亡中生成受到了质疑,但另一方面,该化合物可能不利地调控参与肿瘤表型的发生和维持的信号转导途径的关键蛋白因子的活性,导致其活化,所述蛋白因子诸如蛋白磷酸酶2A[Neviani等人,Cancer Cell 8:355-368,2005;Neviani等人,J Clin Invest117:2408-2421,2007],所谓的MAPK(丝裂原活化蛋白激酶(Mitogen-activated proteinkinase))途径的酶[Ubai等人,Anticancer Res 27:75-88,2007;Estrada-Bernal等人,Neuro Oncol 14:405-415,2012]、PI3K/AKT级联物[Zheng等人,J Cell Biochem 111:218-228,2010;Liu等人,Clin Cancer Res 16:3182-3192,2010]和14-3-3适应性蛋白(adaptive protein)[Woodcock等人,Cell Signal 22:1291-1299,2010],仅举几例。
尽管这些观察结果表明在临床前模型中的抗肿瘤作用,因此允许它们进行进一步的研究以评估它们在人类治疗中的用途,但自其被批准上市以来,其禁忌症确实包括处于活跃期的赘生物以及免疫缺陷,包括可能由化疗剂诱导的继发性免疫缺陷。
此外,尽管表明免疫抑制例如用于治疗免疫介导的疾病或预防排斥,但免疫抑制可能增加宿主对感染或甚至肿瘤的易感性;因此,免疫抑制应始终被考虑在内,并被尽可能地最小化。
具有类似于FTY720的结构的分子已被描述于文献中。
在文章“Inhibitors of the interaction of thyroid hormone receptor andcoactivators:preliminary structure–activity relationships”L.A.Arnold等人,JMed Chem.2007 Nov 1;50(22):5269-5280中,公开了1-苯基丙酮衍生物显示细胞毒性活性,尽管主要针对ARO细胞系(未分化甲状腺癌(anaplastic thyroid cancer)细胞)。
文章“Dyclonine and alverine citrate enhance the cytotoxic effects ofproteasome inhibitor MG132 on breast cancer cells”,D.Ju等人,Int J MolMed.2009 Feb,23(2):205-9和“Dyclonine enhances the cytotoxic effect ofproteasome inhibitor bortezomib in multiple myeloma cells”,D.Ju等人,MOLECULARMEDICINE REPORTS 10:2609-2612,2014报道了具有下式的达克罗宁分子作为癌症治疗中的佐剂的性质:
达克罗宁(Dyclonine)。
具体地,在所引用的两篇文章的第一篇中,研究了达克罗宁在乳腺癌中的活性,而在第二篇中,研究了针对多发性骨髓瘤的活性。在这两种情况下,体外研究得出结论,达克罗宁能够显著提高MG132蛋白酶抑制剂(已知用于治疗乳腺癌)和药物硼替佐米(已知用于治疗多发性骨髓瘤)对靶细胞的细胞毒性效力,但单独的达克罗宁具有非常有限的细胞毒性作用。
因此,本发明的一个目的是通过设计对肿瘤细胞显示促凋亡作用,具有高效力并且同时不具有免疫抑制性质的分子来提供替代的解决方案。
发明概述
上文的目的通过合成和研究通式(I)的1-苯基丙酮化合物来实现
在体外的瘤形成细胞模型中且在不存在免疫抑制作用的情况下,该化合物已被表明通过细胞凋亡诱导细胞死亡,其中:
X是亚甲基基团(-CH2-)或选自由O、S和Se组成的组的原子,
n是从4至6的整数,
A是选自由4-吗啉基、1-哌啶基和4-甲基-1-哌嗪基组成的组的取代基,并且A任选地被(C1-C3)烷基或(C1-C3)酰基基团取代,
条件是当X是CH2时,n等于5,
该化合物用于作为治疗乳腺癌、慢性淋巴性白血病(CLL)或成神经细胞瘤的抗肿瘤剂使用。
本发明人还合成了导致对肿瘤细胞具有细胞凋亡活性的新的1-苯基丙酮衍生化合物。
因此,在另一方面,本发明涉及式(I)的化合物:
其中:
X是亚甲基基团(-CH2-)或选自由O、S和Se组成的组的原子,
n是从4至6的整数,
A是选自由4-吗啉基、1-哌啶基和4-甲基-1-哌嗪基组成的组的取代基,并且A任选地被(C1-C3)烷基或(C1-C3)酰基基团取代,
条件是
当X是O时,A是4-甲基-1-哌嗪基,并且n等于6,
当X是S且n是5时,则A是4-甲基-1-哌嗪基,
当X是Se且A是1-哌啶基时,则n是6,
当X是CH2时,n等于5,并且A是4-甲基-1-哌嗪基或4-吗啉基。
在另一个方面,本发明涉及式(I)的化合物:
其中:
X是亚甲基基团(-CH2-)或选自由O、S和Se组成的组的原子,
n是从4至6的整数,
A是选自由4-吗啉基、1-哌啶基和4-甲基-1-哌嗪基组成的组的取代基,并且A任选地被(C1-C3)烷基或(C1-C3)酰基基团取代,
条件是
当X是O时,A是4-甲基-1-哌嗪基,并且n等于6,
当X是S且n是5时,则A是4-甲基-1-哌嗪基或4-吗啉基,
当X是Se且A是1-哌啶基时,则n是6,
当X是CH2时,n等于5,并且A是4-甲基-1-哌嗪基或4-吗啉基,该化合物用于作为药物使用。
在另一个方面,本发明涉及一种药物组合物,所述药物组合物包含作为药物的式(I)的化合物及其药学上可接受的媒介物。
在又另一个方面,本发明涉及式(I)的化合物
其中:
X是亚甲基基团(-CH2-)或选自由O、S和Se组成的组的原子,
n是从4至6的整数,
A是选自由4-吗啉基、1-哌啶基和4-甲基-1-哌嗪基组成的组的取代基,并且A任选地被(C1-C3)烷基或(C1-C3)酰基基团取代,
条件是
当X是O时,A是4-甲基-1-哌嗪基或1-哌啶基,并且n等于6,
当X是CH2时,n是5,该化合物用于作为抗肿瘤剂使用。
优选地,所述抗肿瘤治疗是针对乳腺癌、肝癌、慢性淋巴性白血病(CLL)或成神经细胞瘤。
附图简述
图1示出了旨在评估本发明化合物的免疫抑制特性并且通过与现有技术的化合物的免疫抑制特性比较的测试的结果。
发明详述
在本发明的化合物中,取代基A的任选的取代基C3-烷基可以是正丙基或异丙基。
本发明涉及式(I)的1-苯基丙酮化合物
其中
X是亚甲基基团(-CH2-)或选自由O、S和Se组成的组的原子,
n是从4至6的整数,
A是选自由4-吗啉基、1-哌啶基和4-甲基-1-哌嗪基组成的组的取代基,并且A任选地被(C1-C3)烷基或(C1-C3)酰基基团取代,
条件是当X是CH2时,n等于5,
该化合物用于作为治疗乳腺癌、慢性淋巴性白血病(CLL)或成神经细胞瘤的抗肿瘤剂使用。
在治疗乳腺癌、慢性淋巴性白血病(CLL)或成神经细胞瘤方面,本发明的化合物优选是
-其中X是S、Se或CH2,更优选S的化合物;
-其中n是5或6的化合物。
A任选地被(C1-C3)烷基或(C1-C3)酰基取代基取代。
优选地,在治疗乳腺癌、慢性淋巴性白血病(CLL)或成神经细胞瘤方面,式(I)的化合物选自由以下组成的组:
更优选地,在治疗乳腺癌、慢性淋巴性白血病(CLL)或成神经细胞瘤方面,式(I)的化合物选自由以下组成的组:
化合物1(AF08),1-(4-(己氧基)苯基)-3-吗啉代丙-1-酮,
化合物3(AF07),1-(4-(己氧基)苯基)-3-(哌啶-1-基)丙-1-酮,
化合物4(CC12),1-(4-(庚氧基)苯基)-3-(哌啶-1-基)丙-1-酮,
化合物5(AI01),1-(4-(庚氧基)苯基)-3-(4-甲基哌嗪-1-基)丙-1-酮,
化合物7(VP158),1-(4-(己硫基)苯基)-3-吗啉代丙-1-酮,
化合物8(FT017),1-(4-(庚硫基)苯基)-3-吗啉代丙-1-酮,
化合物9(MC12),1-(4-(戊硫基)苯基)-3-(哌啶-1-基)丙-1-酮,
化合物10(VP157),1-(4-(己硫基)苯基)-3-(哌啶-1-基)丙-1-酮,
化合物11(FT018),1-(4-(庚硫基)苯基)-3-(哌啶-1-基)丙-1-酮,
化合物13(FT016),1-(4-(己硫基)苯基)-3-(4-甲基哌嗪-1-基)丙-1-酮,
化合物14(FT019),1-(4-(庚硫基)苯基)-3-(4-甲基哌嗪-1-基)丙-1-酮,
化合物16(GR377),1-(4-(己硒基)苯基)-3-吗啉代丙-1-酮,
化合物17(GR386),1-(4-(庚硒基)苯基)-3-吗啉代丙-1-酮,
化合物20(GR387),1-(4-(庚硒基)苯基)-3-(哌啶-1-基)丙-1-酮,
化合物23(GR388),1-(4-(庚硒基)苯基)-3-(4-甲基哌嗪-1-基)丙-1-酮,
化合物24(GR390),1-(4-庚基苯基)-3-吗啉代丙-1-酮,
化合物25(GR391),1-(4-庚基苯基)-3-(哌啶-1-基)丙-1-酮,和
化合物26(GR392),1-(4-庚基苯基)-3-(4-甲基哌嗪-1-基)丙-1-酮。
甚至更优选地,在治疗乳腺癌、慢性淋巴性白血病(CLL)或成神经细胞瘤方面,式(I)的化合物选自由以下组成的组:
化合物1(AF08),1-(4-(己氧基)苯基)-3-吗啉代丙-1-酮,
化合物5(AI01),1-(4-(庚氧基)苯基)-3-(4-甲基哌嗪-1-基)丙-1-酮,
化合物7(VP158),1-(4-(己硫基)苯基)-3-吗啉代丙-1-酮,
化合物8(FT017),1-(4-(庚硫基)苯基)-3-吗啉代丙-1-酮,
化合物9(MC12),1-(4-(戊硫基)苯基)-3-(哌啶-1-基)丙-1-酮,
化合物10(VP157),1-(4-(己硫基)苯基)-3-(哌啶-1-基)丙-1-酮,
化合物11(FT018),1-(4-(庚硫基)苯基)-3-(哌啶-1-基)丙-1-酮,
化合物13(FT016),1-(4-(己硫基)苯基)-3-(4-甲基哌嗪-1-基)丙-1-酮,
化合物14(FT019),1-(4-(庚硫基)苯基)-3-(4-甲基哌嗪-1-基)丙-1-酮,
化合物17(GR386),1-(4-(庚硒基)苯基)-3-吗啉代丙-1-酮,
化合物20(GR387),1-(4-(庚硒基)苯基)-3-(哌啶-1-基)丙-1-酮,
化合物23(GR388),1-(4-(庚硒基)苯基)-3-(4-甲基哌嗪-1-基)丙-1-酮,
化合物24(GR390),1-(4-庚基苯基)-3-吗啉代丙-1-酮,
化合物25(GR391),1-(4-庚基苯基)-3-(哌啶-1-基)丙-1-酮,和
化合物26(GR392),1-(4-庚基苯基)-3-(4-甲基哌嗪-1-基)丙-1-酮。
本发明人还合成了导致对肿瘤细胞具有细胞凋亡活性的新的1-苯基丙酮化合物。
在另一方面,本发明涉及式(I)的1-苯基丙酮化合物:
其中:
X是亚甲基基团(-CH2-)或选自由O、S和Se组成的组的原子,
n是从4至6的整数,
A是选自由4-吗啉基、1-哌啶基和4-甲基-1-哌嗪基组成的组的取代基,并且A任选地被(C1-C3)烷基或(C1-C3)酰基基团取代,
条件是
当X是O时,A是4-甲基-1-哌嗪基,并且n等于6,
当X是S且n是5时,则A是4-甲基-1-哌嗪基,
当X是Se且A是1-哌啶基时,则n是6,
当X是CH2时,n等于5,并且A是4-甲基-1-哌嗪基或4-吗啉基。
优选地,在本发明的1-苯基丙酮化合物中,X选自由S、Se或CH2组成的组,更优选地X是S。
A任选地被(C1-C3)烷基或(C1-C3)酰基取代基取代。
有利地,本发明的化合物是其中n是5或6的化合物。
式(I)的新的化合物优选是选自由以下组成的组的化合物:
化合物5(AI01),1-(4-(庚氧基)苯基)-3-(4-甲基哌嗪-1-基)丙-1-酮,
化合物6(MD63),3-吗啉代-1-(4-(戊硫基)苯基)丙-1-酮,
化合物8(FT017),1-(4-(庚硫基)苯基)-3-吗啉代丙-1-酮,
化合物9(MC12),1-(4-(戊硫基)苯基)-3-(哌啶-1-基)丙-1-酮,
化合物11(FT018),1-(4-(庚硫基)苯基)-3-(哌啶-1-基)丙-1-酮,
化合物12(FT013),3-(4-甲基哌嗪-1-基)-1-(4-(戊硫基)苯基)丙-1-酮,
化合物13(FT016),1-(4-(己硫基)苯基)-3-(4-甲基哌嗪-1-基)丙-1-酮,
化合物14(FT019),1-(4-(庚硫基)苯基)-3-(4-甲基哌嗪-1-基)丙-1-酮,
化合物15(GR376),3-吗啉代-1-(4-(戊硒基)苯基)丙-1-酮,
化合物16(GR377),1-(4-(己硒基)苯基)-3-吗啉代丙-1-酮,
化合物17(GR386),1-(4-(庚硒基)苯基)-3-吗啉代丙-1-酮,
化合物20(GR387),1-(4-(庚硒基)苯基)-3-(哌啶-1-基)丙-1-酮,
化合物21(GR379),3-(4-甲基哌嗪-1-基)-1-(4-(戊硒基)苯基)丙-1-酮,
化合物22(GR383),1-(4-(己硒基)苯基)-3-(4-甲基哌嗪-1-基)丙-1-酮,
化合物23(GR388),1-(4-(庚硒基)苯基)-3-(4-甲基哌嗪-1-基)丙-1-酮,
化合物24(GR390),1-(4-庚基苯基)-3-吗啉代丙-1-酮,
化合物26(GR392),1-(4-庚基苯基)-3-(4-甲基哌嗪-1-基)丙-1-酮。
更优选地,式(I)的新的化合物优选地是选自由以下组成的组的化合物:
化合物5(AI01),1-(4-(庚氧基)苯基)-3-(4-甲基哌嗪-1-基)丙-1-酮,
化合物8(FT017),1-(4-(庚硫基)苯基)-3-吗啉代丙-1-酮,
化合物9(MC12),1-(4-(戊硫基)苯基)-3-(哌啶-1-基)丙-1-酮,
化合物11(FT018),1-(4-(庚硫基)苯基)-3-(哌啶-1-基)丙-1-酮,
化合物13(FT016),1-(4-(己硫基)苯基)-3-(4-甲基哌嗪-1-基)丙-1-酮,
化合物14(FT019),1-(4-(庚硫基)苯基)-3-(4-甲基哌嗪-1-基)丙-1-酮,
化合物17(GR386),1-(4-(庚硒基)苯基)-3-吗啉代丙-1-酮,
化合物20(GR387),1-(4-(庚硒基)苯基)-3-(哌啶-1-基)丙-1-酮,
化合物23(GR388),1-(4-(庚硒基)苯基)-3-(4-甲基哌嗪-1-基)丙-1-酮,
化合物24(GR390),1-(4-庚基苯基)-3-吗啉代丙-1-酮,和
化合物26(GR392),1-(4-庚基苯基)-3-(4-甲基哌嗪-1-基)丙-1-酮。
甚至更优选地,式(I)的新的化合物优选地是选自由以下组成的组的化合物:
化合物8(FT017),1-(4-(庚硫基)苯基)-3-吗啉代丙-1-酮,
化合物11(FT018),1-(4-(庚硫基)苯基)-3-(哌啶-1-基)丙-1-酮,
化合物13(FT016),1-(4-(己硫基)苯基)-3-(4-甲基哌嗪-1-基)丙-1-酮,
化合物14(FT019),1-(4-(庚硫基)苯基)-3-(4-甲基哌嗪-1-基)丙-1-酮,
化合物17(GR386),1-(4-(庚硒基)苯基)-3-吗啉代丙-1-酮,
化合物24(GR390),1-(4-庚基苯基)-3-吗啉代丙-1-酮,
化合物26(GR392),1-(4-庚基苯基)-3-(4-甲基哌嗪-1-基)丙-1-酮。
在另一个方面,本发明涉及式(I)的化合物:
其中:
X是亚甲基基团(-CH2-)或选自由O、S和Se组成的组的原子,
n是从4至6的整数,
A是选自由4-吗啉基、1-哌啶基和4-甲基-1-哌嗪基组成的组的取代基,并且A任选地被(C1-C3)烷基或(C1-C3)酰基基团取代,
条件是
当X是O时,A是4-甲基-1-哌嗪基,并且n等于6,
当X是S且n是5时,则A是4-甲基-1-哌嗪基或4-吗啉基,
当X是Se且A是1-哌啶基时,则n是6,
当X是CH2时,n等于5,并且A是4-甲基-1-哌嗪基或4-吗啉基,该化合物用于作为药物使用。
优选地,在本发明的作为药物的1-苯基丙酮化合物中,X选自由S、Se或CH2组成的组,更优选地X是S。
A任选地被(C1-C3)烷基或(C1-C3)酰基取代基取代。
有利地,本发明的作为药物的化合物是其中n是5或6的化合物。
作为药物的式(I)的化合物优选地是选自由以下组成的组的化合物:
化合物5(AI01),1-(4-(庚氧基)苯基)-3-(4-甲基哌嗪-1-基)丙-1-酮,
化合物6(MD63),3-吗啉代-1-(4-(戊硫基)苯基)丙-1-酮,
化合物7(VP158),1-(4-(己硫基)苯基)-3-吗啉代丙-1-酮,
化合物8(FT017),1-(4-(庚硫基)苯基)-3-吗啉代丙-1-酮,
化合物9(MC12),1-(4-(戊硫基)苯基)-3-(哌啶-1-基)丙-1-酮,
化合物11(FT018),1-(4-(庚硫基)苯基)-3-(哌啶-1-基)丙-1-酮,
化合物12(FT013),3-(4-甲基哌嗪-1-基)-1-(4-(戊硫基)苯基)丙-1-酮,
化合物13(FT016),1-(4-(己硫基)苯基)-3-(4-甲基哌嗪-1-基)丙-1-酮,
化合物14(FT019),1-(4-(庚硫基)苯基)-3-(4-甲基哌嗪-1-基)丙-1-酮,
化合物15(GR376),3-吗啉代-1-(4-(戊硒基)苯基)丙-1-酮,
化合物16(GR377),1-(4-(己硒基)苯基)-3-吗啉代丙-1-酮,
化合物17(GR386),1-(4-(庚硒基)苯基)-3-吗啉代丙-1-酮,
化合物20(GR387),1-(4-(庚硒基)苯基)-3-(哌啶-1-基)丙-1-酮,
化合物21(GR379),3-(4-甲基哌嗪-1-基)-1-(4-(戊硒基)苯基)丙-1-酮,
化合物22(GR383),1-(4-(己硒基)苯基)-3-(4-甲基哌嗪-1-基)丙-1-酮,
化合物23(GR388),1-(4-(庚硒基)苯基)-3-(4-甲基哌嗪-1-基)丙-1-酮,
化合物24(GR390),1-(4-庚基苯基)-3-吗啉代丙-1-酮,和
化合物26(GR392),1-(4-庚基苯基)-3-(4-甲基哌嗪-1-基)丙-1-酮。
更优选地,作为药物的新的式(I)的化合物优选地是选自由以下组成的组的化合物:
化合物5(AI01),1-(4-(庚氧基)苯基)-3-(4-甲基哌嗪-1-基)丙-1-酮,
化合物7(VP158),1-(4-(己硫基)苯基)-3-吗啉代丙-1-酮,
化合物8(FT017),1-(4-(庚硫基)苯基)-3-吗啉代丙-1-酮,
化合物9(MC12),1-(4-(戊硫基)苯基)-3-(哌啶-1-基)丙-1-酮,
化合物11(FT018),1-(4-(庚硫基)苯基)-3-(哌啶-1-基)丙-1-酮,
化合物13(FT016),1-(4-(己硫基)苯基)-3-(4-甲基哌嗪-1-基)丙-1-酮,
化合物14(FT019),1-(4-(庚硫基)苯基)-3-(4-甲基哌嗪-1-基)丙-1-酮,
化合物17(GR386),1-(4-(庚硒基)苯基)-3-吗啉代丙-1-酮,
化合物20(GR387),1-(4-(庚硒基)苯基)-3-(哌啶-1-基)丙-1-酮,
化合物23(GR388),1-(4-(庚硒基)苯基)-3-(4-甲基哌嗪-1-基)丙-1-酮,
化合物24(GR390),1-(4-庚基苯基)-3-吗啉代丙-1-酮,和
化合物26(GR392),1-(4-庚基苯基)-3-(4-甲基哌嗪-1-基)丙-1-酮。
甚至更优选地,作为药物的新的式(I)的化合物优选地是选自由以下组成的组的化合物:
化合物7(VP158),1-(4-(己硫基)苯基)-3-吗啉代丙-1-酮,
化合物8(FT017),1-(4-(庚硫基)苯基)-3-吗啉代丙-1-酮,
化合物11(FT018),1-(4-(庚硫基)苯基)-3-(哌啶-1-基)丙-1-酮,
化合物13(FT016),1-(4-(己硫基)苯基)-3-(4-甲基哌嗪-1-基)丙-1-酮,
化合物14(FT019),1-(4-(庚硫基)苯基)-3-(4-甲基哌嗪-1-基)丙-1-酮,
化合物17(GR386),1-(4-(庚硒基)苯基)-3-吗啉代丙-1-酮,
化合物24(GR390),1-(4-庚基苯基)-3-吗啉代丙-1-酮,
化合物26(GR392),1-(4-庚基苯基)-3-(4-甲基哌嗪-1-基)丙-1-酮。
在另一个方面,本发明涉及一种药物组合物,所述药物组合物包含作为药物的式(I)的化合物,及药学上可接受的媒介物。
本发明的化合物其本身或其药学上可接受的盐可在医学(medicine)中被采用。然后,它们可以与药学上可接受的媒介物和任选的合适的赋形剂组合,以获得药物组合物。术语“药学上可接受的媒介物”意指包括在施用本发明的化合物中采用的溶剂、技术助剂(technological aids)、稀释剂等。
这样的药物组合物可以通过肠胃外、口服、含服、舌下、经鼻、直肠、局部或透皮途径施用。
适合口服施用的本发明的组合物将便利地呈离散单位的形式,诸如片剂、胶囊、扁囊剂(cachet)、粉剂或颗粒,或者甚至作为液体中的悬浮剂。
片剂还可以包含合适的药用赋形剂,诸如预胶化淀粉(pre-gelatinizedstarch)、微晶纤维素、乙二醇淀粉钠(sodium glycol starch)、滑石、乳糖、硬脂酸镁、蔗糖、硬脂酸、甘露糖醇。
用于肠胃外施用的组合物将便利地包含无菌制备物。
用于局部施用的组合物将便利地呈乳霜、糊剂、油、软膏、乳液、泡沫、凝胶、滴剂、喷雾溶液和透皮贴剂的形式。
在又另一个方面,本发明涉及式(I)的化合物
其中:
X是亚甲基基团(-CH2-)或选自由O、S和Se组成的组的原子,
n是从4至6的整数,
A是选自由4-吗啉基、1-哌啶基和4-甲基-1-哌嗪基组成的组的取代基,并且A任选地被(C1-C3)烷基或(C1-C3)酰基基团取代,
条件是
当X是O时,A是4-甲基-1-哌嗪基或1-哌啶基,并且n等于6,
当X是C时,n是5,该化合物用于作为抗肿瘤剂使用。
优选地,抗肿瘤治疗针对乳腺癌、肝癌、慢性淋巴性白血病(CLL)或成神经细胞瘤。
优选地,在用于作为抗肿瘤剂使用的本发明的1-苯基丙酮化合物中,X选自由S、Se或CH2组成的组,更优选地X是S。
A任选地被(C1-C3)烷基或(C1-C3)酰基取代基取代。
有利地,用于作为抗肿瘤剂使用的本发明化合物是其中n是5或6的化合物。
优选地,用于作为抗肿瘤剂使用的本发明的1-苯基丙酮化合物是选自由以下组成的组的化合物:
化合物4(CC12),1-(4-(庚氧基)苯基)-3-(哌啶-1-基)丙-1-酮,
化合物5(AI01),1-(4-(庚氧基)苯基)-3-(4-甲基哌嗪-1-基)丙-1-酮,
化合物6(MD63),3-吗啉代-1-(4-(戊硫基)苯基)丙-1-酮,
化合物7(VP158),1-(4-(己硫基)苯基)-3-吗啉代丙-1-酮,
化合物8(FT017),1-(4-(庚硫基)苯基)-3-吗啉代丙-1-酮,
化合物9(MC12),1-(4-(戊硫基)苯基)-3-(哌啶-1-基)丙-1-酮,
化合物10(VP157),1-(4-(己硫基)苯基)-3-(哌啶-1-基)丙-1-酮,
化合物11(FT018),1-(4-(庚硫基)苯基)-3-(哌啶-1-基)丙-1-酮,
化合物12(FT013),3-(4-甲基哌嗪-1-基)-1-(4-(戊硫基)苯基)丙-1-酮,
化合物13(FT016),1-(4-(己硫基)苯基)-3-(4-甲基哌嗪-1-基)丙-1-酮,
化合物14(FT019),1-(4-(庚硫基)苯基)-3-(4-甲基哌嗪-1-基)丙-1-酮,
化合物15(GR376),3-吗啉代-1-(4-(戊硒基)苯基)丙-1-酮,
化合物16(GR377),1-(4-(己硒基)苯基)-3-吗啉代丙-1-酮,
化合物17(GR386),1-(4-(庚硒基)苯基)-3-吗啉代丙-1-酮,
化合物18(GR378),1-(4-(戊硒基)苯基)-3-(哌啶-1-基)丙-1-酮,
化合物19(GR381),1-(4-(己硒基)苯基)-3-(哌啶-1-基)丙-1-酮,
化合物20(GR387),1-(4-(庚硒基)苯基)-3-(哌啶-1-基)丙-1-酮,
化合物21(GR379),3-(4-甲基哌嗪-1-基)-1-(4-(戊硒基)苯基)丙-1-酮,
化合物22(GR383),1-(4-(己硒基)苯基)-3-(4-甲基哌嗪-1-基)丙-1-酮,
化合物23(GR388),1-(4-(庚硒基)苯基)-3-(4-甲基哌嗪-1-基)丙-1-酮,
化合物24(GR390),1-(4-庚基苯基)-3-吗啉代丙-1-酮,
化合物25(GR391),1-(4-庚基苯基)-3-(哌啶-1-基)丙-1-酮,和
化合物26(GR392),1-(4-庚基苯基)-3-(4-甲基哌嗪-1-基)丙-1-酮。
更优选地,其是选自由以下组成的组的用于抗肿瘤用途的化合物:
化合物4(CC12),1-(4-(庚氧基)苯基)-3-(哌啶-1-基)丙-1-酮,
化合物5(AI01),1-(4-(庚氧基)苯基)-3-(4-甲基哌嗪-1-基)丙-1-酮,
化合物7(VP158),1-(4-(己硫基)苯基)-3-吗啉代丙-1-酮,
化合物8(FT017),1-(4-(庚硫基)苯基)-3-吗啉代丙-1-酮,
化合物9(MC12),1-(4-(戊硫基)苯基)-3-(哌啶-1-基)丙-1-酮,
化合物10(VP157),1-(4-(己硫基)苯基)-3-(哌啶-1-基)丙-1-酮,
化合物11(FT018),1-(4-(庚硫基)苯基)-3-(哌啶-1-基)丙-1-酮,
化合物13(FT016),1-(4-(己硫基)苯基)-3-(4-甲基哌嗪-1-基)丙-1-酮,
化合物14(FT019),1-(4-(庚硫基)苯基)-3-(4-甲基哌嗪-1-基)丙-1-酮,
化合物16(GR377),1-(4-(己硒基)苯基)-3-吗啉代丙-1-酮,
化合物17(GR386),1-(4-(庚硒基)苯基)-3-吗啉代丙-1-酮,
化合物20(GR387),1-(4-(庚硒基)苯基)-3-(哌啶-1-基)丙-1-酮,
化合物23(GR388),1-(4-(庚硒基)苯基)-3-(4-甲基哌嗪-1-基)丙-1-酮,
化合物24(GR390),1-(4-庚基苯基)-3-吗啉代丙-1-酮,
化合物25(GR391),1-(4-庚基苯基)-3-(哌啶-1-基)丙-1-酮,和
化合物26(GR392),1-(4-庚基苯基)-3-(4-甲基哌嗪-1-基)丙-1-酮。
甚至更优选地,用于作为抗肿瘤剂使用的式(I)的化合物选自由以下组成的组:
化合物5(AI01),1-(4-(庚氧基)苯基)-3-(4-甲基哌嗪-1-基)丙-1-酮,
化合物7(VP158),1-(4-(己硫基)苯基)-3-吗啉代丙-1-酮,
化合物8(FT017),1-(4-(庚硫基)苯基)-3-吗啉代丙-1-酮,
化合物9(MC12),1-(4-(戊硫基)苯基)-3-(哌啶-1-基)丙-1-酮,
化合物10(VP157),1-(4-(己硫基)苯基)-3-(哌啶-1-基)丙-1-酮,
化合物11(FT018),1-(4-(庚硫基)苯基)-3-(哌啶-1-基)丙-1-酮,
化合物13(FT016),1-(4-(己硫基)苯基)-3-(4-甲基哌嗪-1-基)丙-1-酮,
化合物14(FT019),1-(4-(庚硫基)苯基)-3-(4-甲基哌嗪-1-基)丙-1-酮,
化合物17(GR386),1-(4-(庚硒基)苯基)-3-吗啉代丙-1-酮,
化合物20(GR387),1-(4-(庚硒基)苯基)-3-(哌啶-1-基)丙-1-酮,
化合物23(GR388),1-(4-(庚硒基)苯基)-3-(4-甲基哌嗪-1-基)丙-1-酮,
化合物24(GR390),1-(4-庚基苯基)-3-吗啉代丙-1-酮,
化合物25(GR391),1-(4-庚基苯基)-3-(哌啶-1-基)丙-1-酮,和
化合物26(GR392),1-(4-庚基苯基)-3-(4-甲基哌嗪-1-基)丙-1-酮。
根据本发明,优选且特别地用于乳腺癌、慢性淋巴性白血病或成神经细胞瘤的新的化合物或用于作为药物或作为抗肿瘤剂使用的化合物通过容易工业扩展的简单的方法获得,并且该方法避免使用冗长且昂贵的制备步骤,获得高收率的稳定的医药级化合物。
现在通过说明而非限制的方式接着描述用于制备本发明的化合物并评估其效力的实验部分。
实验部分
实施例1
制备式(I)的化合物
用于制备其中X是氧的式(I)的1-苯基丙酮化合物的一般步骤
苯基烷基醚中间体由在碳酸钾(2当量)的存在下、在乙腈中的苯酚和合适的1-溴烷烃(例如,1-溴戊烷、1-溴己烷或1-溴庚烷,以1当量的量)之间的反应获得。将混合物在室温搅拌持续5h,然后通过过滤除去由此形成的固体,并通过旋转蒸发蒸发溶剂。将得到的苯基烷基醚中间体与3-溴丙酰氯(2当量)和三氯化铝(3当量)在冰浴的1,2-二氯乙烷中反应。通过将反应物倒入水中而使反应终止,并用二乙基醚提取期望的中间体。将有机层分离并进行旋转蒸发以获得对位酰化的苯基烷基醚衍生物。然后将由此合成的中间体用甲苯中的合适的环胺(吗啉、哌啶或N-甲基哌嗪,2当量)、碘化钾(2当量)和碳酸钙(3当量)处理。将混合物回流,持续12小时。冷却后,通过过滤除去固体,并通过旋转蒸发蒸发溶剂。然后将残留物分散至二氯甲烷中,并将混合物用10%的氢氧化钠溶液洗涤。通过旋转蒸发使有机层蒸发,提供如下文所示的期望的化合物。收率:68-78%。
化合物1(AF08),1-(4-(己氧基)苯基)-3-吗啉代丙-1-酮
1H-NMR(400MHz,CDCl3)δ:7.95(d,2H,PhH),6.92(d,2H,PhH),4.00(t,2H,OCH2),3.71(m,4H,OCH2),3.15(t,2H,COCH2),2.85(t,2H,NCH2),2.54(m,4H,NCH2),1.82(m,2H,CH2),1.4-1.2(m,6H,CH2),0.92(t,3H,CH3).
13C-NMR{1H}(100MHz,CDCl3)δ:196.5,162.2,129.3,113.2,76.2,67.3,65.9,52.8,52.7,34.5,30.5,28.0,24.6,21.6,13.0.m/z(ESI):320.2.
收率:72%。纯度(HPLC):97%。
化合物2(CC11),1-(4-(庚氧基)苯基)-3-吗啉代丙-1-酮
1H-NMR(400MHz,CDCl3)δ:7.95(d,2H,PhH),6.94(d,2H,PhH),4.04(t,2H,OCH2),3.74(m,4H,OCH2),3.16(t,2H,COCH2),2.85(t,2H,NCH2),2.54(m,4H,NCH2),1.83(m,2H,CH2),1.5-1.2(m,8H,CH2),0.92(t,3H,CH3).
13C-NMR{1H}(100MHz,CDCl3)δ:197.5.163.2,130.3,129.7,114.2,68.3,67.0,53.8,53.7,35.6,31.7,29.1,29.0,25.9,22.6,14.1.m/z(ESI):334.2.
收率:68%。纯度(HPLC):97%。
化合物3(AF07),1-(4-(己氧基)苯基)-3-(哌啶-1-基)丙-1-酮
1H-NMR(400MHz,CDCl3)δ:7.80(d,2H,PhH),6.94(d,2H,PhH),4.04(t,2H,OCH2),3.18(m,4H,NCH2),3.11(t,2H,COCH2),2.82(t,2H,CH2),1.82(m,2H,CH2),1.63(m,4H,CH2),1.49(m,4H,CH2),1.37(m,4H,CH2),0.93(t,3H,CH3).
13C-NMR{1H}(100MHz,CDCl3)δ:195.5,161.8,129.0,128.5,12.9,75.9,66.9,53.3,52.8,30.3,27.8,24.6,24.7,21.3,19.0,12.8.m/z(ESI):318.2.
收率:75%。纯度(HPLC):98%。
化合物4(CC12),1-(4-(庚氧基)苯基)-3-(哌啶-1-基)丙-1-酮
1H-NMR(400MHz,CDCl3)δ:7.81(d,2H,PhH),6.92(d,2H,PhH),4.01(t,2H,OCH2),3.18(m,4H,NCH2),3.10(t,2H,COCH2),2.83(t,2H,CH2),1.82(m,2H,CH2),1.62(m,6H,CH2),1.50(m,4H,CH2),1.32(m,4H,CH2),0.99(t,3H,CH3).
13C-NMR{1H}(100MHz,CDCl3)δ:198.0,163.1,130.3,129.8,114.2,68.2,54.6,54.2,36.1,31.7,29.1,29.0,26.0,25.9,24.3,22.6,14.1.m/z(ESI):332.3.
收率:76%。纯度(HPLC):97%。
化合物5(AI01),1-(4-(庚氧基)苯基)-3-(4-甲基哌嗪-1-基)丙-1-酮
1H-NMR(400MHz,CDCl3)δ:7.89(d,2H,PhH),6.90(d,2H,PhH),4.03(t,2H,OCH2),3.12(t,2H,COCH2),2.83(t,2H,NCH2),2.62(m,4H,NCH2),2.50(m,4H,NCH2),2.33(s,3H,CH3),1.81(m,2H,CH2),1.4-1.2(m,8H,CH2),0.92(t,3H,CH3).
13C-NMR{1H}(100MHz,CDCl3)δ:196.2,162.2,129.1,114.1,76.9,66.7,65.1,52.8,51.1,45.1,32.5,33.2,29.4,28.7,24.6,21.2,13.1.m/z(ESI):347.3.
收率:70%。纯度(HPLC):97%。
用于制备其中X是硫的式(I)的1-苯基丙酮化合物的一般步骤
苯基烷基硫醚中间体由在室温、在氢氧化钾(2当量)的存在下、在乙醇中的苯硫酚和合适的1-溴烷烃(例如1-溴戊烷、1-溴己烷或1-溴庚烷,1当量)之间的反应获得。将混合物在室温搅拌持续5h,然后通过过滤除去由此形成的固体,并通过旋转蒸发蒸发溶剂。然后将得到的苯基烷基硫醚中间体与3-溴丙酰氯(2当量)和三氯化铝(3当量)在冰浴的1,2-二氯乙烷中反应。通过将反应物倒入水中而使反应终止,并用二乙基醚提取期望的中间体。将有机层分离并进行旋转蒸发,以获得对位酰化的苯基烷基硫醚。将如此合成的中间体用甲苯中的合适的环胺(吗啉、哌啶或N-甲基哌嗪,2当量)、碘化钾(2当量)和碳酸钙(3当量)处理。将混合物回流,持续12小时。冷却后,通过过滤除去固体并通过旋转蒸发蒸发溶剂。将残留物分散至二氯甲烷中,并用10%的氢氧化钠溶液洗涤混合物。通过旋转蒸发使有机层蒸发以提供期望的化合物。收率:65-75%。
化合物6(MD63),3-吗啉代-1-(4-(戊硫基)苯基)丙-1-酮
1H-NMR(400MHz,CDCl3)δ:7.83(d,2H,PhH),7.28(d,2H,PhH),3.69(t,4H,OCH2),3.12(t,2H,COCH2),2.97(t,2H,CH2),2.81(t,2H,SCH2),2.49(m,4H,NCH2),1.69(m,4H,CH2),1.37(m,2H,CH2),0.90(t,3H,CH3).
13C-NMR(100MHz,CDCl3)δ:197.9,145.1,133.5,128.4,126.3,66.8,53.7,53.6,35.8,31.8,31.0,28.4,22.1,13.8.m/z(ESI):322.2.
收率:72%。纯度(HPLC):98%。
化合物7(VP158),1-(4-(己硫基)苯基)-3-吗啉代丙-1-酮
1H-NMR(400MHz,CDCl3)δ:7.84(d,2H,PhH),7.19(d,2H,PhH),3.69(t,4H,OCH2),3.10(t,2H,COCH2),2.98(t,2H,CH2),2.81(t,2H,SCH2),2.44(m,4H,NCH2),1.7-1.5(m,6H,CH2),1.37(m,2H,CH2),0.90(t,3H,CH3).
13C-NMR(100MHz,CDCl3)δ:197.9,145.2,137.1,133.4,128.8,68.9,53.7,35.7,33.6,31.9,31.3,30.5,29.1,28.5,22.5.m/z(ESI):336.2.
收率:69%。纯度(HPLC):97%。
化合物8(FT17),1-(4-(庚硫基)苯基)-3-吗啉代丙-1-酮
1H-NMR(400MHz,CDCl3)δ:7.82(d,2H,PhH),7.22(d,2H,PhH),3.66(t,4H,OCH2),3.12(t,2H,COCH2),2.92(t,2H,CH2),2.79(t,2H,SCH2),2.44(m,4H,NCH2),1.6-1.5(m,8H,CH2),1.34(m,2H,CH2),0.98(t,3H,CH3).
13C-NMR(100MHz,CDCl3)δ:197.7,145.1,136.1,133.2,128.9,69.9,54.7,36.7,35.4,33.6,31.9,31.0,30.1,29.4,28.4,22.5.m/z(ESI):350.2.
收率:65%。纯度(HPLC):97%。
化合物9(MC12),1-(4-(戊硫基)苯基)-3-(哌啶-1-基)丙-1-酮
1H-NMR(400MHz,CDCl3)δ:7.74(d,2H,PhH),6.94(d,2H,PhH),3.13(m,4H,NCH2),3.11(t,2H,COCH2),3.04(t,2H,SCH2),2.72(t,2H,CH2),1.82(m,2H,CH2),1.63(m,4H,CH2),1.49(m,2H,CH2),1.37(m,2H,CH2),0.93(t,3H.CH3).
13C-NMR{1H}(100MHz,CDCl3)δ:198.0,163.1,130.3,129.8,14.2,68.2,54.6,54.2,34.1,31.7,29.3,26.7,24.3,22.6,14.1m/z(ESI):320.2.
收率:72%。纯度(HPLC):98%。
化合物10(VP157),1-(4-(己硫基)苯基)-3-(哌啶-1-基)丙-1-酮
1H-NMR(400MHz,CDCl3)δ:7.70(d,2H,PhH),6.94(d,2H,PhH),3.12(m,4H,NCH2),3.09(t,2H,COCH2),3.04(t,2H,SCH2),2.71(t,2H,CH2),1.81(m,2H,CH2),1.6-1.5(m,4H,CH2),1.49(m,4H,CH2),1.37(m,2H,CH2),0.93(t,3H,CH3).
13C-NMR(100MHz,CDCl3)δ:198.2,145.1,133.4,128.8,126.3,54.5,53.9,45.1,36.0,33.6,31.9,31.3,28.9,28.5,25.7,22.5.m/z(ESI):334.2.
收率:71%。纯度(HPLC):97%。
化合物11(FT018),1-(4-(庚硫基)苯基)-3-(哌啶-1-基)丙-1-酮
1H-NMR(400MHz,CDCl3)δ:7.72(d,2H,PhH),6.93(d,2H,PhH),3.11(m,4H,NCH2),3.08(t,2H,COCH2),3.00(t,2H,SCH2),2.72(t,2H,CH2),1.81(m,2H,CH2),1.6-1.5(m,4H,CH2),1.49(m,6H,CH2),1.33(m,2H,CH2),0.90(t,3H,CH3).
13C-NMR(100MHz,CDCl3)δ:197.9,145.0,136.0,133.1,128.8,69.9,62.3,54.7,36.2,35.8,33.5,31.8,31.1,30.2,29.7,28.2,22.4.m/z(ESI):349.2.
收率:68%。纯度(HPLC):97%。
化合物12(FT013),3-(4-甲基哌嗪-1-基)-1-(4-(戊硫基)苯基)丙-1-酮
1H-NMR(400MHz,CDCl3)δ:7.75(d,2H,PhH),6.90(d,2H,PhH),3.16(t,2H,COCH2),3.03(t,2H,SCH2),2.84(t,2H,NCH2),2.60(m,4H,NCH2),2.51(m,4H,NCH2),2.23(s,3H,CH3),1.82(m,2H,CH2),1.4-1.2(m,4H,CH2),0.97(t,3H,CH3).
13C-NMR{1H}(100MHz,CDCl3)δ:193.2,161.2,132.3,111.6,75.3,67.9,65.1,52.7,51.6,45.2,34.5,31.6,29.2,22.2,13.8.m/z(ESI):335.2.
收率:75%。纯度(HPLC):98%。
化合物13(FT016),1-(4-(己硫基)苯基)-3-(4-甲基哌嗪-1-基)丙-1-酮
1H-NMR(400MHz,CDCl3)δ:7.75(d,2H,PhH),6.92(d,2H,PhH),3.15(t,2H,COCH2),3.03(t,2H,SCH2),2.84(t,2H,NCH2),2.64(m,4H,NCH2),2.52(m,4H,NCH2),2.27(s,3H,CH3),1.82(m,2H,CH2),1.4-1.2(m,6H,CH2),0.92(t,3H,CH3).
13C-NMR{1H}(100MHz,CDCl3)δ:196.1,164.1,130.3,112.1,75.2,68.9,65.3,52.1,51.7,45.5,34.9,31.2,28.0,23.2,21.2,14.6.rn/z(ESI):349.2.
收率:72%。纯度(HPLC):97%。
化合物14(FT19),1-(4-(庚硫基)苯基)-3-(4-甲基哌嗪-1-基)丙-1-酮
1H-NMR(400MHz,CDCl3)δ:7.78(d,2H,PhH),6.90(d,2H,PhH),3.11(t,2H,COCH2),3.01(t,2H,SCH2),2.87(t,2H,NCH2),2.63(m,4H,NCH2),2.52(m,4H,NCH2),2.23(s,3H,CH3),1.82(m,2H,CH2),1.4-1.2(m,8H,CH2),0.99(t,3H,CH3).
13C-NMR{1H}(100MHz,CDCl3)δ:190.3,168.2,130.1,111.4,75.4,69.0,65.4,52.8.51.2,49.3,34.8,31.0,29.9,28.4,23.7,21.2.13.9.m/z(ESI):363.2.
收率:70%。纯度(HPLC):97%。
用于制备其中X是硒的式(I)的1-苯基丙酮化合物的一般步骤
将适量的二苯基联硒化物(diphenyl diselenide)溶解在乙醇中,并将得到的溶液置于冰浴中。小心地加入硼氢化钠(4当量),同时保持其为冷的并进行搅拌。20分钟后,向混合物中加入合适的1-溴烷烃(例如,1-溴戊烷、1-溴己烷或1-溴庚烷,1当量)。5h后,通过加入水终止反应,并通过旋转蒸发去除乙醇。将所得的残余物分散在二乙基醚中,并用水洗涤有机层。通过旋转蒸发去除二乙基醚以获得苯基烷基硒醚。将此中间体与3-溴丙酰氯(2当量)和三氯化铝(3当量)在冰浴的1,2-二氯乙烷中反应。通过将反应物倒入水中而使反应终止,并用二乙基醚提取期望的中间体。将有机层分离并进行旋转蒸发以获得对位酰化的苯基烷基硒醚。将如此合成的中间体用甲苯中的合适的环胺(吗啉、哌啶或N-甲基哌嗪,2当量)、碘化钾(2当量)和碳酸钙(3当量)处理。将混合物回流,持续12小时。冷却后,通过过滤去除固体并通过旋转蒸发蒸发溶剂。然后将残余物分散至二氯甲烷中,并用10%的氢氧化钠溶液洗涤混合物。通过旋转蒸发使有机层蒸发以获得期望的化合物。收率:72-80%。
化合物15(GR376),3-吗啉代-1-(4-(戊硒基)苯基)丙-1-酮
1H-NMR(400MHz,CDCl3)δ:7.76(d,2H,PhH),7.28(d,2H,PhH),3.69(t,4H,OCH2),3.12(t,2H,COCH2),3.01(t,2H,SeCH2),2.92(t,2H,NCH2),2.49(m,4H,NCH2),1.69(m,4H,CH2),1.37(m,2H,CH2),0.90(t,3H,CH3).
13C-NMR(100MHz,CDCl3)δ:196.2,145.4,133.5,128.2,126.3,66.7,53.2,53.1,35.2,31.2,31.1,28.7,22.2,13.9.m/z(ESI):370.2.
收率:73%。纯度(HPLC):98%。
化合物16(GR377),1-(4-(己硒基)苯基)-3-吗啉代丙-1-酮
1H-NMR(400MHz,CDCl3)δ:7.75(d,2H,PhH),7.29(d,2H,PhH),3.64(t,4H,OCH2),3.12(t,2H,COCH2),3.02(t,2H,SeCH2),2.91(t,2H,NCH2),2.49(m,4H,NCH2),1.69(m,6H,CH2),1.37(m,2H,CH2),0.90(1,3H,CH3).
13C-NMR(100MHz,CDCl3)δ:196.2,145.4,132.5,128.2,125.2,66.7,53.6,53.1,35.1,31.2,31.1,28.7,25.2,22.2,13.9.m/z(ESI):384.1.
收率:79%。纯度(HPLC):97%。
化合物17(GR386),1-(4-(庚硒基)苯基)-3-吗啉代丙-1-酮
1H-NMR(400MHz,CDCl3)δ:7.73(d,2H,PhH),7.29(d,2H,PhH),3.62(t,4H,OCH2),3.12(t,2H,COCH2),3.03(t,2H,SeCH2),2.91(t,2H,NCH2),2.47(m,4H,NCH2),1.7-1.5(m,8H,CH2),1.38(m,2H,CH2),0.91(t,3H,CH3).
13C-NMR(100MHz,CDCl3)δ:198.1,145.2,132.1,128.6,125.1,66.8,53.2,49.5,35.3,31.0,31.2,28.9,25.1,22.0,14.2.m/z(ESI):398.2.
收率:80%。纯度(HPLC):97%。
化合物18(GR378),1-(4-(戊硒基)苯基)-3-(哌啶-1-基)丙-1-酮
1H-NMR(400MHz,CDCl3)δ:7.74(d,2H,PhH),6.94(d,2H,PhH),3.15(m,4H,NCH2),3.11(t,2H,COCH2),3.01(m,2H,SeCH2),2.82(t,2H,CH2),1.80(m,2H,CH2),1.63(m,2H,CH2),1.46(m,4H,CH2),1.37(m,2H,CH2),0.93(t,3H,CH3).
13C-NMR{1H}(100MHz,CDCl3)δ:198.0,162.1,131.2,129.3,140.1,68.1,53.2,54.6,34.2,30.5,29.2,26.7,24.2,22.1,14.0.m/z(ESI):368.1.
收率:72%。纯度(HPLC):97%。
化合物19(GR381),1-(4-(己硒5基)苯基)-3-(哌啶-1-基)丙-1-酮
1H-NMR(400MHz,CDCl3)δ:7.74(d,2H,PhH),6.92(d,2H,PhH),3.11(m,4H,NCH2)3.08(t,2H,COCH2),3.02(m,2H,SeCH2),2.81(t,2H,CH2),1.79(m,2H,CH2),1.62(m,4H,CH2),1.45(m,6H,CH2),1.32(m,2H,CH2),0.91(t,3H,CH3).
13C-NMR{1H)(100MHz,CDCl3)δ:195.2,161.6,132.1,130.2,141.1,67.4,53.1,51.4,38.2,33.1,30.5,29.8,26.1,23.9,19.8,14.1.m/z(ESI):382.2.
收率:76%。纯度(HPLC):98%。
化合物20(GR387),1-(4-(庚硒基)苯基)-3-(哌啶-1-基)丙-1-酮
1H-NMR(400MHz,CDCl3)δ:7.74(d,2H,PhH),6.92(d,2H,PhH),3.12(m,4H,NCH2),3.09(t,2H,COCH2),3.01(1,2H,SeCH2),2.81(t,2H,CH2),1.79(m,4H,CH2),1.7-1.4(m,10H,CH2),0.91(t,3H,CH3).
13C-NMR{1H}(100MHz,CDCl3)δ:191.2,162.2,131.5,132.1,142.2,68.2,51.0,50.4,38.1,35.2,32.4,31.5,29.0,26.2,23.8,19.7.14.2.m/z(ESI):396.2.
收率:75%。纯度(HPLC):96%。
化合物21(GR379),3-(4-甲基哌嗪-1-基)-1-(4-(戊硒基)苯基)丙-1-酮
1H-NMR(400MHz,CDCl3)δ:7.75(d,2H,PhH),6.90(d,2H,PhH),3.16(t,2H,COCH2),3.01(t,2H,SeCH2),2.84(t,2H,NCH2),2.60(m,4H,NCH2),2.51(m,4H,NCH2),2.21(s,3H,CH3),1.82(m,2H,CH2),1.4-1.2(m,4H,CH2),0.97(t,3H,CH3).
13C-NMR{1H}(100MHz,CDCl3)δ:195.8,161.1,132.2,111.6,75.2,68.1,64.2,51.7,51.5,45.1,33.2,31.4,29.1,22.1,14.8.m/z(ESI):383.2.
收率:72%。纯度(HPLC):97%。
化合物22(GR383),1-(4-(己硒基)苯基)-3-(4-甲基哌嗪-1-基)丙-1-酮
1H-NMR(400MHz,CDCl3)δ:7.74(d,2H,PhH),6.91(d,2H,PhH),3.13(t,2H,COCH2),3.01(t,2H,SeCH2),2.81(t,2H,NCH2),2.60(m,4H,NCH2),2.48(m,4H,NCH2),2.22(s,3H,CH3),1.81(m,2H,CH2),1.5-1.2(m,6H,CH2),0.93(t,3H,CH3).
13C-NMR{1H}(100MHz,CDCl3)δ:193.2,161.0,132.0,111.5,75.1,68.4,64.9,52.9,51.0,45.2,37.1,33.1,31.7,29.1,22.0,13.8.m/z(ESI):397.2.
收率:79%。纯度(HPLC):98%。
化合物23(GR388),1-(4-(庚硒基)苯基)-3-(4-甲基哌嗪-1-基)丙-1-酮
1H-NMH(400MHz,CDCl3)δ:7.74(d,2H,PhH),6.91(d,2H,PhH),3.13(t,2H,COCH2),3.01(t,2H,SeCH2),2.81(t,2H,NCH2),2.60(m,4H,NCH2),2.48(m,4H,NCH2),2.22(s,3H,CH3),1.81(m,2H,CH2),1.5-1.2(m,8H,CH2),0.93(t,3H,CH3).
13C-NMR{1H}(100MHz,CDCl3)δ:196.4,160.2,131.2,111.2,75.3,68.2,64.3,52.1,51.9,45.1,37.5,33.3,32.7,31.4,29.8,22.2,13.9.m/z(ESI):411.2.
收率:76%。纯度(HPLC):97%。
用于制备其中X是亚甲基,CH2的式(I)的1-苯基丙酮化合物的一般步骤
将合适的烷基苯(例如戊基苯、己基苯或庚基苯)与3-溴丙酰氯(2当量)和三氯化铝(3当量)在冰浴的1,2-二氯乙烷中反应。通过将反应物倒入水中而使反应终止,并用二乙基醚提取期望的中间体。将有机层分离并进行旋转蒸发。然后将如此合成的中间体用甲苯中的合适的环胺(吗啉、哌啶或N-甲基哌嗪,2当量)、碘化钾(2当量)和碳酸钙(3当量)处理。将混合物回流,持续12小时。冷却后,通过过滤去除固体并通过旋转蒸发蒸发溶剂。将残余物分散至二氯甲烷中并用10%的氢氧化钠溶液洗涤混合物。通过旋转蒸发使有机层蒸发以提供期望的化合物。收率:61-75%。
化合物24(GR390),1-(4-庚基苯基)-3-吗啉代丙-1-酮
1H-NMR(400MHz,CDCl3)δ:7.75(d,2H,PhH),7.08(d,2H,PhH),3.69(t,4H,OCH2),3.12(t,2H,COCH2),2.87(t,2H,NCH2),2.62(t,2H,PhCH2),2.48(m,4H,NCH2),1.74(m,6H,CH2),1.30(m,4H,CH2),0.90(t,3H,CH3).
13C-NMR(100MHz,CDCl3)δ:191.5,157.2,143.1,131.6,124.3,67.5,53.2,51.4,34.3,32.0,31.3,28.4,25.6,23.0,22.8,14.1.m/z(ESI):318.2.
收率:61%。纯度(HPLC):97%。
化合物25(GR391),1-(4-庚基苯基)-3-(哌啶-1-基)丙-1-酮
1H-NMR(400MHz,CDCl3)δ:7.74(d,2H,PhH),6.91(d,2H,PhH),3.09(t,2H,COCH2),2.99(m,4H,NCH2),2.55(t,2H,PhCH2),2.84(t,2H,CH2),1.75(m,4H,CH2),1.62(m,4H,CH2),1.41(m,6H,CH2),1.31(m,4H,CH2),0.96(t,3H,CH3).
13C-NMR(100MHz,CDCl3)δ:190.4,157.5,142.2,133.1,125.2,68.7,54.1,52.2,37.0,32.1,31.5,29.7,28.4,27.2,25.0,24.2,13.5.m/z(ESI):316.3.
收率:72%。纯度(HPLC):98%。
化合物26(GR392),1-(4-庚基苯基)-3-(4-甲基哌嗪-1-基)丙-1-酮
1H-NMR(400MHz,CDCl3)δ:7.72(d,2H,PhH),6.90(d,2H,PhH),3.12(t,2H,COCH2),2.82(t,2H,NCH2),2.62(m,4H,NCH2),2.49(t,2H,PhCH2),2.43(m,4H,NCH2),2.21(s,3H,CH3),1.81(m,2H,CH2),1.5-1.2(m,8H,CH2),0.93(t,3H,CH3).
13C-NMR{1H}(100MHz,CDCl3)δ:196.3,161.4,131.3,111.6,78.2,67.1,66.2,54.2,51.7,45.2,34.5,33.3,31.7,31.5,29.7,21.2,15.1.m/z(ESI):331.3.
收率:75%。纯度(HPLC):97%。
实施例2
对肿瘤细胞的体外促凋亡作用的评估
使用流式细胞荧光术(Flow cytofluorometry)评估本发明的一些化合物诱导细胞死亡的能力,特别是关于细胞凋亡的能力。细胞凋亡现象以质膜的形态学改变为特征,该形态改变是质膜中的磷脂,磷脂酰丝氨酸(PS)从细胞质侧易位至细胞外表面的结果。在钙离子的存在下,膜联蛋白V蛋白表现出对PS的高亲和力,成为用于细胞凋亡检测的可靠的标志物。膜联蛋白被检测是因为其与特定的荧光染料缀合,从而允许区分凋亡和坏死现象,坏死现象改为由荧光染料碘化丙锭测量,碘化丙锭自由地穿透具有受损的质膜的细胞。
使用了取自患有慢性淋巴性白血病(CLL)的患者的原发性淋巴细胞肿瘤细胞和成神经细胞瘤(SK-N-BE)、肝癌(HepG2和HUH7.5)和乳腺癌(MDA-MB-231)的人源化细胞系。
将HepG2(每孔2x105个细胞)、HUH7.5和MDA-MB-231(每孔1.5x105个细胞)细胞接种在6孔板上的10%FBS的Dulbecco改良的Eagle培养基(Dulbecco’s Modified EagleMedium)(DMEM)中,并在37℃在5%CO2气氛中培养。24小时后,去除培养基并用含有测试化合物的DMEM代替,测试化合物预先溶解在100%二甲基亚砜中并稀释,使其在细胞孵育溶液中的最终浓度为0.5%(v/v)。孵育30分钟后,加入10%的FBS,并孵育细胞24小时,然后用胰蛋白酶解除贴壁,并通过细胞荧光光度计(cytofluorimeter)分析。将CLL细胞(每孔1x106个细胞)接种在12孔板上的10%FBS的RPMI-1640培养基中,并在37℃含有5%CO2的湿化的(humified)气氛中培养。向该培养基中加入测试化合物,并进行孵育,持续24小时,孵育时间后通过细胞荧光光度计分析细胞。
在对来自CLL患者的外周血的静脉抽取物肝素化处理后,分离白血病淋巴细胞,用1:3的比用盐水稀释,在Ficoll/Hypaque(F/H)密度梯度上分层,在20℃以900rpm离心20分钟(不含制动)。在进一步洗涤2次后,通过在室温以400rpm离心分离浓缩至F/H梯度上部的单核细胞和血小板。将如此获得的单核细胞用PBS洗涤3次,在20℃以400rpm离心10分钟(含制动),并重新悬浮在RPMI 1640中。
在大多数CLL病例中,对于来自外周血的所有单核细胞,白血病B细胞的百分比高于85%。
将从一式三份进行的三个独立的实验中通过细胞荧光法获得的结果列成表格,评估引起50%的细胞凋亡所需的浓度(IC50)和标准偏差。结果在下文表1中示出。
表1
如表1示出的,将细胞暴露于化合物表明:
-理想的烷基链由6或7个碳原子表示,因此n优选是5或6;
-对于具有由硒表示的杂原子的化合物,当碳链含有7个碳原子,即n等于6时,观察到更高的效力;
-赋予分子最高效力的杂原子是S,同样地能够诱导凋亡,而与哌啶、吗啉和甲基哌嗪基团无关;
-在其中杂原子不是硫的化合物中,吗啉基团是赋予更有效的细胞凋亡作用的基团。
此外,如上文讨论的,以D.Ju等人之名引用的两篇文章讨论了与本发明的一些化合物类似、但具有仅4个碳原子的烷氧基链的化合物,达克罗宁的特性。这些文章突出了达克罗宁在诱导乳腺癌和多发性骨髓瘤细胞中细胞凋亡时仅作为蛋白酶体抑制剂作用的增强剂的作用,并且仅在15-30μM的范围内的浓度显示诱导胱天蛋白酶依赖性细胞凋亡的效力(IC50值),远高于本发明化合物有活性的浓度(IC50值从0.55μM至14.23μM的最大值,其中大多数化合物示出了低于3的IC50值)。
实施例3
评估本发明化合物的免疫抑制作用
如引言中讨论的,化合物FTY720对肿瘤细胞表现出细胞毒性作用,同时维持奠定免疫抑制作用的分子机制,所述机制在于S1P受体的降解。为了评估对于在抗肿瘤治疗中潜在使用而言是不期望的这种该机制在本发明的化合物的存在下是否持续存在,通过在相同条件下将这些化合物中的一些与FTY720进行比较而对它们进行了测试。为此,将CLL细胞(5x105/孔)接种在12孔板上的10%FBS的RPMI-1640培养基中,并于37℃、在含有5%CO2的湿化的气氛中培养,向培养物添加各种测试化合物。持续不同的时间(discrete)进行孵育,在孵育结束时使细胞裂解以将蛋白内容物提交至用特异性识别S1P1受体的抗体的蛋白印迹分析(Western blot analysis)。图1中示出的结果清楚地表明,FTY720诱导S1P1受体的快速减少,在孵育3小时时已经明显并且在孵育12小时后甚至更显著(S1P1浓度降低是免疫抑制的原因);相反地,测试的本发明的化合物在测试的所有时间点保持相同受体的表达谱不变。
Claims (23)
2.如权利要求1所述的用途,其中X是S、Se或CH2。
3.如权利要求1或2所述的用途,其中n是5或6。
4.如权利要求1所述的用途,其中所述化合物选自由以下组成的组:
化合物1(AF08),1-(4-(己氧基)苯基)-3-吗啉代丙-1-酮,
化合物2(CC11),1-(4-(庚氧基)苯基)-3-吗啉代丙-1-酮,
化合物3(AF07),1-(4-(己氧基)苯基)-3-(哌啶-1-基)丙-1-酮,
化合物4(CC12),1-(4-(庚氧基)苯基)-3-(哌啶-1-基)丙-1-酮,
化合物5(AI01),1-(4-(庚氧基)苯基)-3-(4-甲基哌嗪-1-基)丙-1-酮,
化合物6(MD63),3-吗啉代-1-(4-(戊硫基)苯基)丙-1-酮,
化合物7(VP158),1-(4-(己硫基)苯基)-3-吗啉代丙-1-酮,
化合物8(FT017),1-(4-(庚硫基)苯基)-3-吗啉代丙-1-酮,
化合物9(MC12),1-(4-(戊硫基)苯基)-3-(哌啶-1-基)丙-1-酮,
化合物10(VP157),1-(4-(己硫基)苯基)-3-(哌啶-1-基)丙-1-酮,
化合物11(FT018),1-(4-(庚硫基)苯基)-3-(哌啶-1-基)丙-1-酮,
化合物12(FT013),3-(4-甲基哌嗪-1-基)-1-(4-(戊硫基)苯基)丙-1-酮,
化合物13(FT016),1-(4-(己硫基)苯基)-3-(4-甲基哌嗪-1-基)丙-1-酮,
化合物14(FT019),1-(4-(庚硫基)苯基)-3-(4-甲基哌嗪-1-基)丙-1-酮,
化合物15(GR376),3-吗啉代-1-(4-(戊硒基)苯基)丙-1-酮,
化合物16(GR377),1-(4-(己硒基)苯基)-3-吗啉代丙-1-酮,
化合物17(GR386),1-(4-(庚硒基)苯基)-3-吗啉代丙-1-酮,
化合物18(GR378),1-(4-(戊硒基)苯基)-3-(哌啶-1-基)丙-1-酮,
化合物19(GR381),1-(4-(己硒基)苯基)-3-(哌啶-1-基)丙-1-酮,
化合物20(GR387),1-(4-(庚硒基)苯基)-3-(哌啶-1-基)丙-1-酮,
化合物21(GR379),3-(4-甲基哌嗪-1-基)-1-(4-(戊硒基)苯基)丙-1-酮,
化合物22(GR383),1-(4-(己硒基)苯基)-3-(4-甲基哌嗪-1-基)丙-1-酮,
化合物23(GR388),1-(4-(庚硒基)苯基)-3-(4-甲基哌嗪-1-基)丙-1-酮,
化合物24(GR390),1-(4-庚基苯基)-3-吗啉代丙-1-酮,
化合物25(GR391),1-(4-庚基苯基)-3-(哌啶-1-基)丙-1-酮,和
化合物26(GR392),1-(4-庚基苯基)-3-(4-甲基哌嗪-1-基)丙-1-酮。
5.如权利要求4所述的用途,其中所述化合物选自由以下组成的组:
化合物1(AF08),1-(4-(己氧基)苯基)-3-吗啉代丙-1-酮,
化合物3(AF07),1-(4-(己氧基)苯基)-3-(哌啶-1-基)丙-1-酮,
化合物4(CC12),1-(4-(庚氧基)苯基)-3-(哌啶-1-基)丙-1-酮,
化合物5(AI01),1-(4-(庚氧基)苯基)-3-(4-甲基哌嗪-1-基)丙-1-酮,
化合物7(VP158),1-(4-(己硫基)苯基)-3-吗啉代丙-1-酮,
化合物8(FT017),1-(4-(庚硫基)苯基)-3-吗啉代丙-1-酮,
化合物9(MC12),1-(4-(戊硫基)苯基)-3-(哌啶-1-基)丙-1-酮,
化合物10(VP157),1-(4-(己硫基)苯基)-3-(哌啶-1-基)丙-1-酮,
化合物11(FT018),1-(4-(庚硫基)苯基)-3-(哌啶-1-基)丙-1-酮,
化合物13(FT016),1-(4-(己硫基)苯基)-3-(4-甲基哌嗪-1-基)丙-1-酮,
化合物14(FT019),1-(4-(庚硫基)苯基)-3-(4-甲基哌嗪-1-基)丙-1-酮,
化合物16(GR377),1-(4-(己硒基)苯基)-3-吗啉代丙-1-酮,
化合物17(GR386),1-(4-(庚硒基)苯基)-3-吗啉代丙-1-酮,
化合物20(GR387),1-(4-(庚硒基)苯基)-3-(哌啶-1-基)丙-1-酮,
化合物23(GR388),1-(4-(庚硒基)苯基)-3-(4-甲基哌嗪-1-基)丙-1-酮,
化合物24(GR390),1-(4-庚基苯基)-3-吗啉代丙-1-酮,
化合物25(GR391),1-(4-庚基苯基)-3-(哌啶-1-基)丙-1-酮,和
化合物26(GR392),1-(4-庚基苯基)-3-(4-甲基哌嗪-1-基)丙-1-酮。
6.如权利要求5所述的用途,其中所述化合物选自由以下组成的组:
化合物1(AF08),1-(4-(己氧基)苯基)-3-吗啉代丙-1-酮,
化合物5(AI01),1-(4-(庚氧基)苯基)-3-(4-甲基哌嗪-1-基)丙-1-酮,
化合物7(VP158),1-(4-(己硫基)苯基)-3-吗啉代丙-1-酮,
化合物8(FT017),1-(4-(庚硫基)苯基)-3-吗啉代丙-1-酮,
化合物9(MC12),1-(4-(戊硫基)苯基)-3-(哌啶-1-基)丙-1-酮,
化合物10(VP157),1-(4-(己硫基)苯基)-3-(哌啶-1-基)丙-1-酮,
化合物11(FT018),1-(4-(庚硫基)苯基)-3-(哌啶-1-基)丙-1-酮,
化合物13(FT016),1-(4-(己硫基)苯基)-3-(4-甲基哌嗪-1-基)丙-1-酮,
化合物14(FT019),1-(4-(庚硫基)苯基)-3-(4-甲基哌嗪-1-基)丙-1-酮,
化合物17(GR386),1-(4-(庚硒基)苯基)-3-吗啉代丙-1-酮,
化合物20(GR387),1-(4-(庚硒基)苯基)-3-(哌啶-1-基)丙-1-酮,
化合物23(GR388),1-(4-(庚硒基)苯基)-3-(4-甲基哌嗪-1-基)丙-1-酮,
化合物24(GR390),1-(4-庚基苯基)-3-吗啉代丙-1-酮,
化合物25(GR391),1-(4-庚基苯基)-3-(哌啶-1-基)丙-1-酮,和
化合物26(GR392),1-(4-庚基苯基)-3-(4-甲基哌嗪-1-基)丙-1-酮。
8.如权利要求7所述的化合物,其中X选自由S、Se或CH2组成的组。
9.如权利要求7或8所述的化合物,其中n是5或6。
10.如权利要求8所述的化合物,其中所述化合物选自由以下组成的组:
化合物5(AI01),1-(4-(庚氧基)苯基)-3-(4-甲基哌嗪-1-基)丙-1-酮,
化合物6(MD63),3-吗啉代-1-(4-(戊硫基)苯基)丙-1-酮,
化合物8(FT017),1-(4-(庚硫基)苯基)-3-吗啉代丙-1-酮,
化合物9(MC12),1-(4-(戊硫基)苯基)-3-(哌啶-1-基)丙-1-酮,
化合物11(FT018),1-(4-(庚硫基)苯基)-3-(哌啶-1-基)丙-1-酮,
化合物12(FT013),3-(4-甲基哌嗪-1-基)-1-(4-(戊硫基)苯基)丙-1-酮,
化合物13(FT016),1-(4-(己硫基)苯基)-3-(4-甲基哌嗪-1-基)丙-1-酮,
化合物14(FT019),1-(4-(庚硫基)苯基)-3-(4-甲基哌嗪-1-基)丙-1-酮,
化合物15(GR376),3-吗啉代-1-(4-(戊硒基)苯基)丙-1-酮,
化合物16(GR377),1-(4-(己硒基)苯基)-3-吗啉代丙-1-酮,
化合物17(GR386),1-(4-(庚硒基)苯基)-3-吗啉代丙-1-酮,
化合物20(GR387),1-(4-(庚硒基)苯基)-3-(哌啶-1-基)丙-1-酮,
化合物21(GR379),3-(4-甲基哌嗪-1-基)-1-(4-(戊硒基)苯基)丙-1-酮,
化合物22(GR383),1-(4-(己硒基)苯基)-3-(4-甲基哌嗪-1-基)丙-1-酮,
化合物23(GR388),1-(4-(庚硒基)苯基)-3-(4-甲基哌嗪-1-基)丙-1-酮,
化合物24(GR390),1-(4-庚基苯基)-3-吗啉代丙-1-酮,和
化合物26(GR392),1-(4-庚基苯基)-3-(4-甲基哌嗪-1-基)丙-1-酮。
11.如权利要求10所述的化合物,其中所述化合物选自由以下组成的组:
化合物5(AI01),1-(4-(庚氧基)苯基)-3-(4-甲基哌嗪-1-基)丙-1-酮,
化合物8(FT017),1-(4-(庚硫基)苯基)-3-吗啉代丙-1-酮,
化合物9(MC12),1-(4-(戊硫基)苯基)-3-(哌啶-1-基)丙-1-酮,
化合物11(FT018),1-(4-(庚硫基)苯基)-3-(哌啶-1-基)丙-1-酮,
化合物13(FT016),1-(4-(己硫基)苯基)-3-(4-甲基哌嗪-1-基)丙-1-酮,
化合物14(FT019),1-(4-(庚硫基)苯基)-3-(4-甲基哌嗪-1-基)丙-1-酮,
化合物17(GR386),1-(4-(庚硒基)苯基)-3-吗啉代丙-1-酮,
化合物20(GR387),1-(4-(庚硒基)苯基)-3-(哌啶-1-基)丙-1-酮,
化合物23(GR388),1-(4-(庚硒基)苯基)-3-(4-甲基哌嗪-1-基)丙-1-酮,
化合物24(GR390),1-(4-庚基苯基)-3-吗啉代丙-1-酮,和
化合物26(GR392),1-(4-庚基苯基)-3-(4-甲基哌嗪-1-基)丙-1-酮。
12.如权利要求11所述的化合物,其中所述化合物选自由以下组成的组:
化合物8(FT017),1-(4-(庚硫基)苯基)-3-吗啉代丙-1-酮,
化合物11(FT018),1-(4-(庚硫基)苯基)-3-(哌啶-1-基)丙-1-酮,
化合物13(FT016),1-(4-(己硫基)苯基)-3-(4-甲基哌嗪-1-基)丙-1-酮,
化合物14(FT019),1-(4-(庚硫基)苯基)-3-(4-甲基哌嗪-1-基)丙-1-酮,
化合物17(GR386),1-(4-(庚硒基)苯基)-3-吗啉代丙-1-酮,
化合物24(GR390),1-(4-庚苯基)-3-吗啉代丙-1-酮,和
化合物26(GR392),1-(4-庚基苯基)-3-(4-甲基哌嗪-1-基)丙-1-酮。
14.如权利要求13所述的药物组合物,其中所述化合物选自由以下组成的组:
化合物5(AI01),1-(4-(庚氧基)苯基)-3-(4-甲基哌嗪-1-基)丙-1-酮,
化合物6(MD63),3-吗啉代-1-(4-(戊硫基)苯基)丙-1-酮,
化合物7(VP158),1-(4-(己硫基)苯基)-3-吗啉代丙-1-酮,
化合物8(FT017),1-(4-(庚硫基)苯基)-3-吗啉代丙-1-酮,
化合物9(MC12),1-(4-(戊硫基)苯基)-3-(哌啶-1-基)丙-1-酮,
化合物11(FT018),1-(4-(庚硫基)苯基)-3-(哌啶-1-基)丙-1-酮,
化合物12(FT013),3-(4-甲基哌嗪-1-基)-1-(4-(戊硫基)苯基)丙-1-酮,
化合物13(FT016),1-(4-(己硫基)苯基)-3-(4-甲基哌嗪-1-基)丙-1-酮,
化合物14(FT019),1-(4-(庚硫基)苯基)-3-(4-甲基哌嗪-1-基)丙-1-酮,
化合物15(GR376),3-吗啉代-1-(4-(戊硒基)苯基)丙-1-酮,
化合物16(GR377),1-(4-(己硒基)苯基)-3-吗啉代丙-1-酮,
化合物17(GR386),1-(4-(庚硒基)苯基)-3-吗啉代丙-1-酮,
化合物20(GR387),1-(4-(庚硒基)苯基)-3-(哌啶-1-基)丙-1-酮,
化合物21(GR379),3-(4-甲基哌嗪-1-基)-1-(4-(戊硒基)苯基)丙-1-酮,
化合物22(GR383),1-(4-(己硒基)苯基)-3-(4-甲基哌嗪-1-基)丙-1-酮,
化合物23(GR388),1-(4-(庚硒基)苯基)-3-(4-甲基哌嗪-1-基)丙-1-酮,
化合物24(GR390),1-(4-庚基苯基)-3-吗啉代丙-1-酮,和
化合物26(GR392),1-(4-庚基苯基)-3-(4-甲基哌嗪-1-基)丙-1-酮。
15.如权利要求14所述的药物组合物,其中所述化合物选自由以下组成的组:
化合物5(AI01),1-(4-(庚氧基)苯基)-3-(4-甲基哌嗪-1-基)丙-1-酮,
化合物7(VP158),1-(4-(己硫基)苯基)-3-吗啉代丙-1-酮,
化合物8(FT017),1-(4-(庚硫基)苯基)-3-吗啉代丙-1-酮,
化合物9(MC12),1-(4-(戊硫基)苯基)-3-(哌啶-1-基)丙-1-酮,
化合物11(FT018),1-(4-(庚硫基)苯基)-3-(哌啶-1-基)丙-1-酮,
化合物13(FT016),1-(4-(己硫基)苯基)-3-(4-甲基哌嗪-1-基)丙-1-酮,
化合物14(FT019),1-(4-(庚硫基)苯基)-3-(4-甲基哌嗪-1-基)丙-1-酮,
化合物17(GR386),1-(4-(庚硒基)苯基)-3-吗啉代丙-1-酮,
化合物20(GR387),1-(4-(庚硒基)苯基)-3-(哌啶-1-基)丙-1-酮,
化合物23(GR388),1-(4-(庚硒基)苯基)-3-(4-甲基哌嗪-1-基)丙-1-酮,
化合物24(GR390),1-(4-庚基苯基)-3-吗啉代丙-1-酮,和
化合物26(GR392),1-(4-庚基苯基)-3-(4-甲基哌嗪-1-基)丙-1-酮。
16.如权利要求15所述的药物组合物,其中所述化合物选自由以下组成的组:
化合物7(VP158),1-(4-(己硫基)苯基)-3-吗啉代丙-1-酮,
化合物8(FT017),1-(4-(庚硫基)苯基)-3-吗啉代丙-1-酮,
化合物11(FT018),1-(4-(庚硫基)苯基)-3-(哌啶-1-基)丙-1-酮,
化合物13(FT016),1-(4-(己硫基)苯基)-3-(4-甲基哌嗪-1-基)丙-1-酮,
化合物14(FT019),1-(4-(庚硫基)苯基)-3-(4-甲基哌嗪-1-基)丙-1-酮,
化合物17(GR386),1-(4-(庚硒基)苯基)-3-吗啉代丙-1-酮,
化合物24(GR390),1-(4-庚基苯基)-3-吗啉代丙-1-酮,和
化合物26(GR392),1-(4-庚基苯基)-3-(4-甲基哌嗪-1-基)丙-1-酮。
18.如权利要求17所述的用途,其中抗肿瘤治疗针对乳腺癌、肝癌、慢性淋巴性白血病或成神经细胞瘤。
19.如权利要求17或18所述的用途,其中X选自由S、Se或CH2组成的组。
20.如权利要求17所述的用途,其中n是5或6。
21.如权利要求17所述的用途,其中所述1-苯基丙酮化合物选自由以下组成的组:
化合物4(CC12),1-(4-(庚氧基)苯基)-3-(哌啶-1-基)丙-1-酮,
化合物5(AI01),1-(4-(庚氧基)苯基)-3-(4-甲基哌嗪-1-基)丙-1-酮,
化合物6(MD63),3-吗啉代-1-(4-(戊硫基)苯基)丙-1-酮,
化合物7(VP158),1-(4-(己硫基)苯基)-3-吗啉代丙-1-酮,
化合物8(FT017),1-(4-(庚硫基)苯基)-3-吗啉代丙-1-酮,
化合物9(MC12),1-(4-(戊硫基)苯基)-3-(哌啶-1-基)丙-1-酮,
化合物10(VP157),1-(4-(己硫基)苯基)-3-(哌啶-1-基)丙-1-酮,
化合物11(FT018),1-(4-(庚硫基)苯基)-3-(哌啶-1-基)丙-1-酮,
化合物12(FT013),3-(4-甲基哌嗪-1-基)-1-(4-(戊硫基)苯基)丙-1-酮,
化合物13(FT016),1-(4-(己硫基)苯基)-3-(4-甲基哌嗪-1-基)丙-1-酮,
化合物14(FT019),1-(4-(庚硫基)苯基)-3-(4-甲基哌嗪-1-基)丙-1-酮,
化合物15(GR376),3-吗啉代-1-(4-(戊硒基)苯基)丙-1-酮,
化合物16(GR377),1-(4-(己硒基)苯基)-3-吗啉代丙-1-酮,
化合物17(GR386),1-(4-(庚硒基)苯基)-3-吗啉代丙-1-酮,
化合物18(GR378),1-(4-(戊硒基)苯基)-3-(哌啶-1-基)丙-1-酮,
化合物19(GR381),1-(4-(己硒基)苯基)-3-(哌啶-1-基)丙-1-酮,
化合物20(GR387),1-(4-(庚硒基)苯基)-3-(哌啶-1-基)丙-1-酮,
化合物21(GR379),3-(4-甲基哌嗪-1-基)-1-(4-(戊硒基)苯基)丙-1-酮,
化合物22(GR383),1-(4-(己硒基)苯基)-3-(4-甲基哌嗪-1-基)丙-1-酮,
化合物23(GR388),1-(4-(庚硒基)苯基)-3-(4-甲基哌嗪-1-基)丙-1-酮,
化合物24(GR390),1-(4-庚基苯基)-3-吗啉代丙-1-酮,
化合物25(GR391),1-(4-庚基苯基)-3-(哌啶-1-基)丙-1-酮,和
化合物26(GR392),1-(4-庚基苯基)-3-(4-甲基哌嗪-1-基)丙-1-酮。
22.如权利要求21所述的用途,其中所述化合物选自由以下组成的组:
化合物4(CC12),1-(4-(庚氧基)苯基)-3-(哌啶-1-基)丙-1-酮,
化合物5(AI01),1-(4-(庚氧基)苯基)-3-(4-甲基哌嗪-1-基)丙-1-酮,
化合物7(VP158),1-(4-(己硫基)苯基)-3-吗啉代丙-1-酮,
化合物8(FT017),1-(4-(庚硫基)苯基)-3-吗啉代丙-1-酮,
化合物9(MC12),1-(4-(戊硫基)苯基)-3-(哌啶-1-基)丙-1-酮,
化合物10(VP157),1-(4-(己硫基)苯基)-3-(哌啶-1-基)丙-1-酮,
化合物11(FT018),1-(4-(庚硫基)苯基)-3-(哌啶-1-基)丙-1-酮,
化合物13(FT016),1-(4-(己硫基)苯基)-3-(4-甲基哌嗪-1-基)丙-1-酮,
化合物14(FT019),1-(4-(庚硫基)苯基)-3-(4-甲基哌嗪-1-基)丙-1-酮,
化合物16(GR377),1-(4-(己硒基)苯基)-3-吗啉代丙-1-酮,
化合物17(GR386),1-(4-(庚硒基)苯基)-3-吗啉代丙-1-酮,
化合物20(GR387),1-(4-(庚硒基)苯基)-3-(哌啶-1-基)丙-1-酮,
化合物23(GR388),1-(4-(庚硒基)苯基)-3-(4-甲基哌嗪-1-基)丙-1-酮,
化合物24(GR390),1-(4-庚基苯基)-3-吗啉代丙-1-酮,
化合物25(GR391),1-(4-庚基苯基)-3-(哌啶-1-基)丙-1-酮,和
化合物26(GR392),1-(4-庚基苯基)-3-(4-甲基哌嗪-1-基)丙-1-酮。
23.如权利要求22所述的用途,其中所述化合物选自由以下组成的组:
化合物5(AI01),1-(4-(庚氧基)苯基)-3-(4-甲基哌嗪-1-基)丙-1-酮,
化合物7(VP158),1-(4-(己硫基)苯基)-3-吗啉代丙-1-酮,
化合物8(FT017),1-(4-(庚硫基)苯基)-3-吗啉代丙-1-酮,
化合物9(MC12),1-(4-(戊硫基)苯基)-3-(哌啶-1-基)丙-1-酮,
化合物10(VP157),1-(4-(己硫基)苯基)-3-(哌啶-1-基)丙-1-酮,
化合物11(FT018),1-(4-(庚硫基)苯基)-3-(哌啶-1-基)丙-1-酮,
化合物13(FT016),1-(4-(己硫基)苯基)-3-(4-甲基哌嗪-1-基)丙-1-酮,
化合物14(FT019),1-(4-(庚硫基)苯基)-3-(4-甲基哌嗪-1-基)丙-1-酮,
化合物17(GR386),1-(4-(庚硒基)苯基)-3-吗啉代丙-1-酮,
化合物20(GR387),1-(4-(庚硒基)苯基)-3-(哌啶-1-基)丙-1-酮,
化合物23(GR388),1-(4-(庚硒基)苯基)-3-(4-甲基哌嗪-1-基)丙-1-酮,
化合物24(GR390),1-(4-庚基苯基)-3-吗啉代丙-1-酮,
化合物25(GR391),1-(4-庚基苯基)-3-(哌啶-1-基)丙-1-酮,和
化合物26(GR392),1-(4-庚基苯基)-3-(4-甲基哌嗪-1-基)丙-1-酮。
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RS61109B1 (sr) | 2020-12-31 |
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BR112019006565A2 (pt) | 2019-07-02 |
RU2019113064A (ru) | 2020-10-30 |
US20200039946A1 (en) | 2020-02-06 |
EP3518927B1 (en) | 2020-08-12 |
WO2018060947A1 (en) | 2018-04-05 |
ES2830749T3 (es) | 2021-06-04 |
RU2765102C2 (ru) | 2022-01-25 |
LT3518927T (lt) | 2021-01-25 |
HUE052039T2 (hu) | 2021-04-28 |
IL265617A (en) | 2019-05-30 |
US11345673B2 (en) | 2022-05-31 |
DK3518927T3 (da) | 2020-11-09 |
AU2017335421A1 (en) | 2019-05-16 |
CA3038008A1 (en) | 2018-04-05 |
EP3518927B9 (en) | 2021-04-07 |
RU2019113064A3 (zh) | 2020-10-30 |
IL265617B (en) | 2022-01-01 |
PT3518927T (pt) | 2020-11-12 |
IT201600098338A1 (it) | 2018-03-30 |
EP3518927A1 (en) | 2019-08-07 |
SI3518927T1 (sl) | 2021-01-29 |
CN110035753A (zh) | 2019-07-19 |
HRP20201769T1 (hr) | 2021-03-19 |
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