JP2000514456A

JP2000514456A - ファルネシルプロテイントランスフェラーゼのチアジオキソベンゾジアゼピン阻害剤

ファルネシルプロテイントランスフェラーゼのチアジオキソベンゾジアゼピン阻害剤

Info

Publication number: JP2000514456A
Authority: JP; Japan
Prior art keywords: tetrahydro; ylmethyl; imidazol; benzothiadiazepine; monohydrochloride
Prior art date: 1996-07-15
Legal status : Ceased

Application number

JP10506095A

Other languages

English (en)

Japanese (ja)

Other versions

JP2000514456A5 (cg-RX-API-DMAC7.html

Inventor

ディング，チャールズ・ゼット

Original Assignee

ブリストル―マイヤーズ・スクイブ・カンパニー

Priority date

1996-07-15

Filing date

1997-07-08

Publication date

2000-10-31

1997-07-08 Application filed by ブリストル―マイヤーズ・スクイブ・カンパニー filed Critical ブリストル―マイヤーズ・スクイブ・カンパニー

2000-10-31 Publication of JP2000514456A publication Critical patent/JP2000514456A/ja

2005-02-10 Publication of JP2000514456A5 publication Critical patent/JP2000514456A5/ja

Status Ceased legal-status Critical Current

Links

125000004030 farnesyl group Chemical group [H]C([*])([H])C([H])=C(C([H])([H])[H])C([H])([H])C([H])([H])C([H])=C(C([H])([H])[H])C([H])([H])C([H])([H])C([H])=C(C([H])([H])[H])C([H])([H])[H] 0.000 title claims description 9
102000004357 Transferases Human genes 0.000 title claims description 8
108090000992 Transferases Proteins 0.000 title claims description 8
239000003112 inhibitor Substances 0.000 title abstract description 6
-1 R 14 Chemical compound 0.000 claims abstract description 53
125000003118 aryl group Chemical group 0.000 claims abstract description 30
125000000217 alkyl group Chemical group 0.000 claims abstract description 29
150000003839 salts Chemical class 0.000 claims abstract description 23
125000000547 substituted alkyl group Chemical group 0.000 claims abstract description 22
125000003710 aryl alkyl group Chemical group 0.000 claims abstract description 19
125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 17
125000005843 halogen group Chemical group 0.000 claims abstract description 12
229910052757 nitrogen Inorganic materials 0.000 claims abstract description 10
239000000651 prodrug Substances 0.000 claims abstract description 10
229940002612 prodrug Drugs 0.000 claims abstract description 10
239000001257 hydrogen Chemical group 0.000 claims abstract description 9
229910052739 hydrogen Inorganic materials 0.000 claims abstract description 9
229910052717 sulfur Inorganic materials 0.000 claims abstract description 8
102000004190 Enzymes Human genes 0.000 claims abstract description 7
108090000790 Enzymes Proteins 0.000 claims abstract description 7
125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 7
125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 7
125000004430 oxygen atom Chemical group O* 0.000 claims abstract description 7
125000004434 sulfur atom Chemical group 0.000 claims abstract description 6
125000003342 alkenyl group Chemical group 0.000 claims abstract description 5
125000000304 alkynyl group Chemical group 0.000 claims abstract description 5
239000012453 solvate Substances 0.000 claims abstract description 5
QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims abstract description 4
229910052799 carbon Inorganic materials 0.000 claims abstract description 4
125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 4
229910052760 oxygen Inorganic materials 0.000 claims abstract description 4
239000001301 oxygen Substances 0.000 claims abstract description 4
125000005017 substituted alkenyl group Chemical group 0.000 claims abstract description 4
125000004426 substituted alkynyl group Chemical group 0.000 claims abstract description 4
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical group [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 3
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 103
150000001875 compounds Chemical class 0.000 claims description 98
125000003287 1H-imidazol-4-ylmethyl group Chemical group [H]N1C([H])=NC(C([H])([H])[*])=C1[H] 0.000 claims description 63
JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 claims description 22
206010028980 Neoplasm Diseases 0.000 claims description 19
238000000034 method Methods 0.000 claims description 19
239000002253 acid Substances 0.000 claims description 16
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 16
201000010099 disease Diseases 0.000 claims description 14
108090000623 proteins and genes Proteins 0.000 claims description 11
102000004169 proteins and genes Human genes 0.000 claims description 11
IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 8
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 8
125000003107 substituted aryl group Chemical group 0.000 claims description 8
125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 7
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
PCTMTFRHKVHKIS-BMFZQQSSSA-N (1s,3r,4e,6e,8e,10e,12e,14e,16e,18s,19r,20r,21s,25r,27r,30r,31r,33s,35r,37s,38r)-3-[(2r,3s,4s,5s,6r)-4-amino-3,5-dihydroxy-6-methyloxan-2-yl]oxy-19,25,27,30,31,33,35,37-octahydroxy-18,20,21-trimethyl-23-oxo-22,39-dioxabicyclo[33.3.1]nonatriaconta-4,6,8,10 Chemical compound C1C=C2C[C@@H](OS(O)(=O)=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2.O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1/C=C/C=C/C=C/C=C/C=C/C=C/C=C/[C@H](C)[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 PCTMTFRHKVHKIS-BMFZQQSSSA-N 0.000 claims description 4
NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 4
MTZQAGJQAFMTAQ-UHFFFAOYSA-N benzoic acid ethyl ester Natural products CCOC(=O)C1=CC=CC=C1 MTZQAGJQAFMTAQ-UHFFFAOYSA-N 0.000 claims description 4
PNZXMIKHJXIPEK-UHFFFAOYSA-N cyclohexanecarboxamide Chemical compound NC(=O)C1CCCCC1 PNZXMIKHJXIPEK-UHFFFAOYSA-N 0.000 claims description 4
230000019491 signal transduction Effects 0.000 claims description 3
239000011593 sulfur Substances 0.000 claims description 3
CICPSCXBPAGDJY-UHFFFAOYSA-N 1,2,5-benzothiadiazepine Chemical compound S1N=CC=NC2=CC=CC=C12 CICPSCXBPAGDJY-UHFFFAOYSA-N 0.000 claims description 2
BIDTYBMVUGZXPQ-UHFFFAOYSA-N 2-[2-[5-(1h-imidazol-5-ylmethyl)-3,4-dihydro-1,2,5-benzothiadiazepin-2-yl]phenoxy]benzonitrile Chemical compound N#CC1=CC=CC=C1OC1=CC=CC=C1N1SC2=CC=CC=C2N(CC=2N=CNC=2)CC1 BIDTYBMVUGZXPQ-UHFFFAOYSA-N 0.000 claims description 2
KKRUQRAUMBARKN-UHFFFAOYSA-N 2-benzyl-5-(1h-imidazol-5-ylmethyl)-3,4-dihydro-1,2,5-benzothiadiazepine Chemical compound C=1NC=NC=1CN(C1=CC=CC=C1S1)CCN1CC1=CC=CC=C1 KKRUQRAUMBARKN-UHFFFAOYSA-N 0.000 claims description 2
125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 2
XKEMFTHKQRYXKW-UHFFFAOYSA-N 3-[8-bromo-5-(1h-imidazol-5-ylmethyl)-3,4-dihydro-1,2,5-benzothiadiazepin-2-yl]benzonitrile Chemical compound C1CN(C=2C=C(C=CC=2)C#N)SC2=CC(Br)=CC=C2N1CC1=CNC=N1 XKEMFTHKQRYXKW-UHFFFAOYSA-N 0.000 claims description 2
XOAKQCOPHMCADA-UHFFFAOYSA-N 4,8-dioxatricyclo[5.1.0.03,5]octane Chemical compound C1C2OC2CC2OC12 XOAKQCOPHMCADA-UHFFFAOYSA-N 0.000 claims description 2
PWWVBQDIHAXGRE-UHFFFAOYSA-N 5-(1h-imidazol-5-ylmethyl)-2-(1,3-thiazol-2-yl)-3,4-dihydro-1,2,5-benzothiadiazepine Chemical compound C=1NC=NC=1CN(C1=CC=CC=C1S1)CCN1C1=NC=CS1 PWWVBQDIHAXGRE-UHFFFAOYSA-N 0.000 claims description 2
NPJLRFNSCACJLF-UHFFFAOYSA-N 5-(1h-imidazol-5-ylmethyl)-2-(2-phenylethyl)-4,7,8,9-tetrahydro-3h-cyclopenta[h][1,2,5]benzothiadiazepine Chemical compound C1CN(CC=2N=CNC=2)C2=CC=3CCCC=3C=C2SN1CCC1=CC=CC=C1 NPJLRFNSCACJLF-UHFFFAOYSA-N 0.000 claims description 2
RRXSVQBTHDGJNA-UHFFFAOYSA-N 5-(1h-imidazol-5-ylmethyl)-2-(2-phenylphenyl)-3,4-dihydro-1,2,5-benzothiadiazepine-8-carbonitrile Chemical compound C1CN(C=2C(=CC=CC=2)C=2C=CC=CC=2)SC2=CC(C#N)=CC=C2N1CC1=CNC=N1 RRXSVQBTHDGJNA-UHFFFAOYSA-N 0.000 claims description 2
UCDFLGARBPQRLO-UHFFFAOYSA-N 5-(1h-imidazol-5-ylmethyl)-2-(naphthalen-1-ylmethyl)-3,4-dihydro-1,2,5-benzothiadiazepine Chemical compound C1CN(CC=2C3=CC=CC=C3C=CC=2)SC2=CC=CC=C2N1CC1=CNC=N1 UCDFLGARBPQRLO-UHFFFAOYSA-N 0.000 claims description 2
AJABEHDAANEOFM-UHFFFAOYSA-N 5-(1h-imidazol-5-ylmethyl)-n,n-dimethyl-2-(2-phenylethyl)-3,4-dihydro-1,2,5-benzothiadiazepin-7-amine Chemical compound C1CN(CC=2N=CNC=2)C2=CC(N(C)C)=CC=C2SN1CCC1=CC=CC=C1 AJABEHDAANEOFM-UHFFFAOYSA-N 0.000 claims description 2
ZAVPGYMJKFHPIK-UHFFFAOYSA-N 7,8-dibromo-5-(1h-imidazol-5-ylmethyl)-2-(2-phenylethyl)-3,4-dihydro-1,2,5-benzothiadiazepine Chemical compound C1CN(CC=2N=CNC=2)C=2C=C(Br)C(Br)=CC=2SN1CCC1=CC=CC=C1 ZAVPGYMJKFHPIK-UHFFFAOYSA-N 0.000 claims description 2
KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 claims description 2
OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 2
102000005454 Dimethylallyltranstransferase Human genes 0.000 claims description 2
108010006731 Dimethylallyltranstransferase Proteins 0.000 claims description 2
QPJVMBTYPHYUOC-UHFFFAOYSA-N Methyl benzoate Natural products COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 claims description 2
125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 claims description 2
UQSPJYQSABLBFQ-UHFFFAOYSA-N n-[5-(1h-imidazol-5-ylmethyl)-2-(2-phenylphenyl)-3,4-dihydro-1,2,5-benzothiadiazepin-7-yl]acetamide Chemical compound C12=CC(NC(=O)C)=CC=C2SN(C=2C(=CC=CC=2)C=2C=CC=CC=2)CCN1CC1=CNC=N1 UQSPJYQSABLBFQ-UHFFFAOYSA-N 0.000 claims description 2
230000004481 post-translational protein modification Effects 0.000 claims description 2
229910052702 rhenium Inorganic materials 0.000 claims description 2
230000002401 inhibitory effect Effects 0.000 claims 3
150000002431 hydrogen Chemical class 0.000 claims 2
QMBXDXUIVJGEPY-UHFFFAOYSA-N 5-(1h-imidazol-5-ylmethyl)-2-(2-phenylphenyl)-3,4-dihydro-1,2,5-benzothiadiazepine Chemical compound C=1NC=NC=1CN(C1=CC=CC=C1S1)CCN1C1=CC=CC=C1C1=CC=CC=C1 QMBXDXUIVJGEPY-UHFFFAOYSA-N 0.000 claims 1
KHBQMWCZKVMBLN-UHFFFAOYSA-N Benzenesulfonamide Chemical compound NS(=O)(=O)C1=CC=CC=C1 KHBQMWCZKVMBLN-UHFFFAOYSA-N 0.000 claims 1
241000124008 Mammalia Species 0.000 claims 1
125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims 1
125000002686 geranylgeranyl group Chemical group [H]C([*])([H])/C([H])=C(C([H])([H])[H])/C([H])([H])C([H])([H])/C([H])=C(C([H])([H])[H])/C([H])([H])C([H])([H])/C([H])=C(C([H])([H])[H])/C([H])([H])C([H])([H])C([H])=C(C([H])([H])[H])C([H])([H])[H] 0.000 claims 1
YFSKQINFBAKJLR-UHFFFAOYSA-N n-[[5-(1h-imidazol-5-ylmethyl)-2-(2-phenylphenyl)-3,4-dihydro-1,2,5-benzothiadiazepin-8-yl]methyl]acetamide Chemical compound C1CN(C=2C(=CC=CC=2)C=2C=CC=CC=2)SC2=CC(CNC(=O)C)=CC=C2N1CC1=CNC=N1 YFSKQINFBAKJLR-UHFFFAOYSA-N 0.000 claims 1
HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 abstract description 11
125000004432 carbon atom Chemical group C* 0.000 abstract description 8
125000004433 nitrogen atom Chemical group N* 0.000 abstract description 5
102000007317 Farnesyltranstransferase Human genes 0.000 abstract description 4
108010007508 Farnesyltranstransferase Proteins 0.000 abstract description 4
HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 abstract description 3
108700042226 ras Genes Proteins 0.000 abstract description 3
RGICCULPCWNRAB-UHFFFAOYSA-N 2-[2-(2-hexoxyethoxy)ethoxy]ethanol Chemical group CCCCCCOCCOCCOCCO RGICCULPCWNRAB-UHFFFAOYSA-N 0.000 abstract 1
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 78
239000000243 solution Substances 0.000 description 52
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 36
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239000000203 mixture Substances 0.000 description 31
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 26
238000006243 chemical reaction Methods 0.000 description 25
229940126062 Compound A Drugs 0.000 description 22
NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 22
239000007787 solid Substances 0.000 description 22
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 18
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239000012044 organic layer Substances 0.000 description 15
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LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 12
239000000460 chlorine Chemical group 0.000 description 12
238000002360 preparation method Methods 0.000 description 12
LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 description 12
239000002904 solvent Substances 0.000 description 11
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
239000002585 base Substances 0.000 description 10
JNGZXGGOCLZBFB-IVCQMTBJSA-N compound E Chemical compound N([C@@H](C)C(=O)N[C@@H]1C(N(C)C2=CC=CC=C2C(C=2C=CC=CC=2)=N1)=O)C(=O)CC1=CC(F)=CC(F)=C1 JNGZXGGOCLZBFB-IVCQMTBJSA-N 0.000 description 10
IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 10
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108010014186 ras Proteins Proteins 0.000 description 10
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229940124530 sulfonamide Drugs 0.000 description 9
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XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 8
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XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
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239000011734 sodium Substances 0.000 description 7
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UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 6
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JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 5
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VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical group O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
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BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
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HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 4
125000001544 thienyl group Chemical group 0.000 description 4
150000003573 thiols Chemical class 0.000 description 4
AQRLNPVMDITEJU-UHFFFAOYSA-N triethylsilane Chemical compound CC[SiH](CC)CC AQRLNPVMDITEJU-UHFFFAOYSA-N 0.000 description 4
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YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
125000004423 acyloxy group Chemical group 0.000 description 3
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