JPH02121924A - Carcinostatic agent effect-enhancing agent - Google Patents
Carcinostatic agent effect-enhancing agentInfo
- Publication number
- JPH02121924A JPH02121924A JP27445088A JP27445088A JPH02121924A JP H02121924 A JPH02121924 A JP H02121924A JP 27445088 A JP27445088 A JP 27445088A JP 27445088 A JP27445088 A JP 27445088A JP H02121924 A JPH02121924 A JP H02121924A
- Authority
- JP
- Japan
- Prior art keywords
- group
- formula
- compound
- acid
- cancer
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 230000003327 cancerostatic effect Effects 0.000 title abstract 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 26
- 150000003839 salts Chemical class 0.000 claims abstract description 10
- 239000004480 active ingredient Substances 0.000 claims abstract description 5
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims abstract description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 3
- 125000002541 furyl group Chemical group 0.000 claims abstract description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 3
- 125000004076 pyridyl group Chemical group 0.000 claims abstract description 3
- 125000001544 thienyl group Chemical group 0.000 claims abstract description 3
- 239000002246 antineoplastic agent Substances 0.000 claims description 39
- 229940041181 antineoplastic drug Drugs 0.000 claims description 37
- 230000000857 drug effect Effects 0.000 claims description 6
- 239000000126 substance Substances 0.000 claims description 4
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- 239000003623 enhancer Substances 0.000 claims description 2
- 230000000694 effects Effects 0.000 abstract description 26
- 206010028980 Neoplasm Diseases 0.000 abstract description 25
- 201000011510 cancer Diseases 0.000 abstract description 23
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 abstract description 14
- 208000016691 refractory malignant neoplasm Diseases 0.000 abstract description 8
- 229940009456 adriamycin Drugs 0.000 abstract description 7
- 239000003795 chemical substances by application Substances 0.000 abstract description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 abstract description 6
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 abstract description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 abstract description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 abstract description 4
- 230000036772 blood pressure Effects 0.000 abstract description 3
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 abstract description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 abstract description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 abstract description 2
- 150000002475 indoles Chemical class 0.000 abstract description 2
- 230000002401 inhibitory effect Effects 0.000 abstract description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 abstract description 2
- 239000011976 maleic acid Substances 0.000 abstract description 2
- 235000006408 oxalic acid Nutrition 0.000 abstract description 2
- 239000011975 tartaric acid Substances 0.000 abstract description 2
- 235000002906 tartaric acid Nutrition 0.000 abstract description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 abstract description 2
- QCXJFISCRQIYID-IAEPZHFASA-N 2-amino-1-n-[(3s,6s,7r,10s,16s)-3-[(2s)-butan-2-yl]-7,11,14-trimethyl-2,5,9,12,15-pentaoxo-10-propan-2-yl-8-oxa-1,4,11,14-tetrazabicyclo[14.3.0]nonadecan-6-yl]-4,6-dimethyl-3-oxo-9-n-[(3s,6s,7r,10s,16s)-7,11,14-trimethyl-2,5,9,12,15-pentaoxo-3,10-di(propa Chemical compound C[C@H]1OC(=O)[C@H](C(C)C)N(C)C(=O)CN(C)C(=O)[C@@H]2CCCN2C(=O)[C@H](C(C)C)NC(=O)[C@H]1NC(=O)C1=C(N=C2C(C(=O)N[C@@H]3C(=O)N[C@H](C(N4CCC[C@H]4C(=O)N(C)CC(=O)N(C)[C@@H](C(C)C)C(=O)O[C@@H]3C)=O)[C@@H](C)CC)=C(N)C(=O)C(C)=C2O2)C2=C(C)C=C1 QCXJFISCRQIYID-IAEPZHFASA-N 0.000 abstract 1
- STQGQHZAVUOBTE-UHFFFAOYSA-N 7-Cyan-hept-2t-en-4,6-diinsaeure Natural products C1=2C(O)=C3C(=O)C=4C(OC)=CC=CC=4C(=O)C3=C(O)C=2CC(O)(C(C)=O)CC1OC1CC(N)C(O)C(C)O1 STQGQHZAVUOBTE-UHFFFAOYSA-N 0.000 abstract 1
- WEAHRLBPCANXCN-UHFFFAOYSA-N Daunomycin Natural products CCC1(O)CC(OC2CC(N)C(O)C(C)O2)c3cc4C(=O)c5c(OC)cccc5C(=O)c4c(O)c3C1 WEAHRLBPCANXCN-UHFFFAOYSA-N 0.000 abstract 1
- 230000002411 adverse Effects 0.000 abstract 1
- 108700002839 cactinomycin Proteins 0.000 abstract 1
- STQGQHZAVUOBTE-VGBVRHCVSA-N daunorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(C)=O)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 STQGQHZAVUOBTE-VGBVRHCVSA-N 0.000 abstract 1
- 231100000614 poison Toxicity 0.000 abstract 1
- 230000007096 poisonous effect Effects 0.000 abstract 1
- 210000004027 cell Anatomy 0.000 description 19
- 238000000034 method Methods 0.000 description 14
- 230000002708 enhancing effect Effects 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 108090000623 proteins and genes Proteins 0.000 description 5
- -1 triethylamine Chemical class 0.000 description 5
- 229960004528 vincristine Drugs 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 4
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000003242 anti bacterial agent Substances 0.000 description 3
- 229940088710 antibiotic agent Drugs 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 230000014759 maintenance of location Effects 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 230000007246 mechanism Effects 0.000 description 3
- 102100033350 ATP-dependent translocase ABCB1 Human genes 0.000 description 2
- 229940127291 Calcium channel antagonist Drugs 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- BRLQWZUYTZBJKN-UHFFFAOYSA-N Epichlorohydrin Chemical compound ClCC1CO1 BRLQWZUYTZBJKN-UHFFFAOYSA-N 0.000 description 2
- 239000004593 Epoxy Substances 0.000 description 2
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 2
- 108010047230 Member 1 Subfamily B ATP Binding Cassette Transporter Proteins 0.000 description 2
- 108010052285 Membrane Proteins Proteins 0.000 description 2
- 102000018697 Membrane Proteins Human genes 0.000 description 2
- NWIBSHFKIJFRCO-WUDYKRTCSA-N Mytomycin Chemical compound C1N2C(C(C(C)=C(N)C3=O)=O)=C3[C@@H](COC(N)=O)[C@@]2(OC)[C@@H]2[C@H]1N2 NWIBSHFKIJFRCO-WUDYKRTCSA-N 0.000 description 2
- 206010033128 Ovarian cancer Diseases 0.000 description 2
- 206010061535 Ovarian neoplasm Diseases 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 239000012980 RPMI-1640 medium Substances 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- RJURFGZVJUQBHK-UHFFFAOYSA-N actinomycin D Natural products CC1OC(=O)C(C(C)C)N(C)C(=O)CN(C)C(=O)C2CCCN2C(=O)C(C(C)C)NC(=O)C1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)NC4C(=O)NC(C(N5CCCC5C(=O)N(C)CC(=O)N(C)C(C(C)C)C(=O)OC4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-UHFFFAOYSA-N 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 238000002512 chemotherapy Methods 0.000 description 2
- ZYVSOIYQKUDENJ-WKSBCEQHSA-N chromomycin A3 Chemical compound O([C@@H]1C[C@@H](O[C@H](C)[C@@H]1OC(C)=O)OC=1C=C2C=C3C[C@H]([C@@H](C(=O)C3=C(O)C2=C(O)C=1C)O[C@@H]1O[C@H](C)[C@@H](O)[C@H](O[C@@H]2O[C@H](C)[C@@H](O)[C@H](O[C@@H]3O[C@@H](C)[C@H](OC(C)=O)[C@@](C)(O)C3)C2)C1)[C@H](OC)C(=O)[C@@H](O)[C@@H](C)O)[C@@H]1C[C@@H](O)[C@@H](OC)[C@@H](C)O1 ZYVSOIYQKUDENJ-WKSBCEQHSA-N 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 239000001963 growth medium Substances 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 230000036457 multidrug resistance Effects 0.000 description 2
- 239000008363 phosphate buffer Substances 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- 238000010898 silica gel chromatography Methods 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 239000003760 tallow Substances 0.000 description 2
- HKKCHULRVUXUBK-UHFFFAOYSA-N 4-hydroxy-1h-indole-2-carbonitrile Chemical compound OC1=CC=CC2=C1C=C(C#N)N2 HKKCHULRVUXUBK-UHFFFAOYSA-N 0.000 description 1
- NLMQHXUGJIAKTH-UHFFFAOYSA-N 4-hydroxyindole Chemical class OC1=CC=CC2=C1C=CN2 NLMQHXUGJIAKTH-UHFFFAOYSA-N 0.000 description 1
- PITHJRRCEANNKJ-UHFFFAOYSA-N Aclacinomycin A Natural products C12=C(O)C=3C(=O)C4=CC=CC=C4C(=O)C=3C=C2C(C(=O)OC)C(CC)(O)CC1OC(OC1C)CC(N(C)C)C1OC(OC1C)CC(O)C1OC1CCC(=O)C(C)O1 PITHJRRCEANNKJ-UHFFFAOYSA-N 0.000 description 1
- 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 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 108010092160 Dactinomycin Proteins 0.000 description 1
- 241000238557 Decapoda Species 0.000 description 1
- 108090000288 Glycoproteins Proteins 0.000 description 1
- 102000003886 Glycoproteins Human genes 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 101710204212 Neocarzinostatin Proteins 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- VGQOVCHZGQWAOI-UHFFFAOYSA-N UNPD55612 Natural products N1C(O)C2CC(C=CC(N)=O)=CN2C(=O)C2=CC=C(C)C(O)=C12 VGQOVCHZGQWAOI-UHFFFAOYSA-N 0.000 description 1
- JXLYSJRDGCGARV-WWYNWVTFSA-N Vinblastine Natural products O=C(O[C@H]1[C@](O)(C(=O)OC)[C@@H]2N(C)c3c(cc(c(OC)c3)[C@]3(C(=O)OC)c4[nH]c5c(c4CCN4C[C@](O)(CC)C[C@H](C3)C4)cccc5)[C@@]32[C@H]2[C@@]1(CC)C=CCN2CC3)C JXLYSJRDGCGARV-WWYNWVTFSA-N 0.000 description 1
- 229940122803 Vinca alkaloid Drugs 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- USZYSDMBJDPRIF-SVEJIMAYSA-N aclacinomycin A Chemical compound O([C@H]1[C@@H](O)C[C@@H](O[C@H]1C)O[C@H]1[C@H](C[C@@H](O[C@H]1C)O[C@H]1C[C@]([C@@H](C2=CC=3C(=O)C4=CC=CC(O)=C4C(=O)C=3C(O)=C21)C(=O)OC)(O)CC)N(C)C)[C@H]1CCC(=O)[C@H](C)O1 USZYSDMBJDPRIF-SVEJIMAYSA-N 0.000 description 1
- 229960004176 aclarubicin Drugs 0.000 description 1
- RJURFGZVJUQBHK-IIXSONLDSA-N actinomycin D Chemical compound C[C@H]1OC(=O)[C@H](C(C)C)N(C)C(=O)CN(C)C(=O)[C@@H]2CCCN2C(=O)[C@@H](C(C)C)NC(=O)[C@H]1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)N[C@@H]4C(=O)N[C@@H](C(N5CCC[C@H]5C(=O)N(C)CC(=O)N(C)[C@@H](C(C)C)C(=O)O[C@@H]4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-IIXSONLDSA-N 0.000 description 1
- 239000003463 adsorbent Substances 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 239000003817 anthracycline antibiotic agent Substances 0.000 description 1
- VGQOVCHZGQWAOI-HYUHUPJXSA-N anthramycin Chemical compound N1[C@@H](O)[C@@H]2CC(\C=C\C(N)=O)=CN2C(=O)C2=CC=C(C)C(O)=C12 VGQOVCHZGQWAOI-HYUHUPJXSA-N 0.000 description 1
- 230000000340 anti-metabolite Effects 0.000 description 1
- 229940100197 antimetabolite Drugs 0.000 description 1
- 239000002256 antimetabolite Substances 0.000 description 1
- 206010003119 arrhythmia Diseases 0.000 description 1
- 230000006793 arrhythmia Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 230000005907 cancer growth Effects 0.000 description 1
- 239000012830 cancer therapeutic Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical class N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 235000005687 corn oil Nutrition 0.000 description 1
- 239000002285 corn oil Substances 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 235000012343 cottonseed oil Nutrition 0.000 description 1
- 239000002385 cottonseed oil Substances 0.000 description 1
- 229960000640 dactinomycin Drugs 0.000 description 1
- CFCUWKMKBJTWLW-UHFFFAOYSA-N deoliosyl-3C-alpha-L-digitoxosyl-MTM Natural products CC=1C(O)=C2C(O)=C3C(=O)C(OC4OC(C)C(O)C(OC5OC(C)C(O)C(OC6OC(C)C(O)C(C)(O)C6)C5)C4)C(C(OC)C(=O)C(O)C(C)O)CC3=CC2=CC=1OC(OC(C)C1O)CC1OC1CC(O)C(O)C(C)O1 CFCUWKMKBJTWLW-UHFFFAOYSA-N 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- GKIPXFAANLTWBM-UHFFFAOYSA-N epibromohydrin Chemical compound BrCC1CO1 GKIPXFAANLTWBM-UHFFFAOYSA-N 0.000 description 1
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 1
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 239000000644 isotonic solution Substances 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- CFCUWKMKBJTWLW-BKHRDMLASA-N mithramycin Chemical compound O([C@@H]1C[C@@H](O[C@H](C)[C@H]1O)OC=1C=C2C=C3C[C@H]([C@@H](C(=O)C3=C(O)C2=C(O)C=1C)O[C@@H]1O[C@H](C)[C@@H](O)[C@H](O[C@@H]2O[C@H](C)[C@H](O)[C@H](O[C@@H]3O[C@H](C)[C@@H](O)[C@@](C)(O)C3)C2)C1)[C@H](OC)C(=O)[C@@H](O)[C@@H](C)O)[C@H]1C[C@@H](O)[C@H](O)[C@@H](C)O1 CFCUWKMKBJTWLW-BKHRDMLASA-N 0.000 description 1
- 229960004857 mitomycin Drugs 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 208000025113 myeloid leukemia Diseases 0.000 description 1
- QZGIWPZCWHMVQL-UIYAJPBUSA-N neocarzinostatin chromophore Chemical compound O1[C@H](C)[C@H](O)[C@H](O)[C@@H](NC)[C@H]1O[C@@H]1C/2=C/C#C[C@H]3O[C@@]3([C@@H]3OC(=O)OC3)C#CC\2=C[C@H]1OC(=O)C1=C(O)C=CC2=C(C)C=C(OC)C=C12 QZGIWPZCWHMVQL-UIYAJPBUSA-N 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 229940021222 peritoneal dialysis isotonic solution Drugs 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229960003171 plicamycin Drugs 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 230000035176 regulation of the force of heart contraction Effects 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- XREXPQGDOPQPAH-QKUPJAQQSA-K trisodium;[(z)-18-[1,3-bis[[(z)-12-sulfonatooxyoctadec-9-enoyl]oxy]propan-2-yloxy]-18-oxooctadec-9-en-7-yl] sulfate Chemical compound [Na+].[Na+].[Na+].CCCCCCC(OS([O-])(=O)=O)C\C=C/CCCCCCCC(=O)OCC(OC(=O)CCCCCCC\C=C/CC(CCCCCC)OS([O-])(=O)=O)COC(=O)CCCCCCC\C=C/CC(CCCCCC)OS([O-])(=O)=O XREXPQGDOPQPAH-QKUPJAQQSA-K 0.000 description 1
- 229960003048 vinblastine Drugs 0.000 description 1
- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 229950009268 zinostatin Drugs 0.000 description 1
Abstract
Description
【発明の詳細な説明】
【産業上の利用分野Ｊ
本発明は、新規化合物およびそれを有効成分として含有
する制癌剤効果増強剤に関する。DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application J] The present invention relates to a novel compound and an anticancer drug effect enhancer containing the same as an active ingredient.
【従来の技術および課題１
癌患者は年々増加し、わが国においては癌による死亡率
が第−位を占め、社会的に癌の治療に対する関心は高い
。[Prior art and problem 1] The number of cancer patients is increasing year by year, and the mortality rate due to cancer is the highest in Japan, and there is a high social interest in cancer treatment.
癌の治療に対する制癌剤の研究開発は従来から活発に行
われており、臨床的にも種々の制癌剤が癌の治療に用い
られている。その効果は年々着実に改善されつつあるが
、多（の場合、癌の増殖を完全に抑制し、癌患者の生存
を長期にわたり維持せしめるには必ずしも満足できる効
果は得られていない、また、複数の制癌剤の組み合わせ
（多剤併用治療）による制癌剤効果増強の試みも、現在
臨床的に多く行われている。しかし、この場合も癌の化
学治療法としては不満足なものであり、新しい視点から
の新しい癌治療剤の開発が切望されているところである
。Research and development of anticancer drugs for the treatment of cancer has been actively carried out, and various anticancer drugs are used clinically for the treatment of cancer. Although its effectiveness has been steadily improving year by year, it has not necessarily achieved a satisfactory effect in completely suppressing cancer growth and maintaining the survival of cancer patients for a long period of time. At present, many attempts are being made clinically to enhance the effects of anticancer drugs by combining anticancer drugs (multidrug combination therapy).However, this is also unsatisfactory as a chemotherapy method for cancer, and research from a new perspective is needed. There is a great need for the development of new cancer therapeutics.
このような事情において、一つの方法としては、−層協
力な制癌剤の開発や、より選択的な目的臓器への制癌剤
の輸送方法の開発等が考えられる。現在、これらの研究
が世界各地においてなされているが、ますますその困難
度を増しているのが現状である。Under these circumstances, one possible method would be to develop a multilayered anticancer drug or a method for more selectively transporting the anticancer drug to the target organ. These studies are currently being carried out all over the world, but the current situation is that they are becoming increasingly difficult.
一方、重要な他の方法として、既存制癌剤の効果増強を
試みる方法がある。特に、臨床上、癌化宇治療法におけ
る重大な問題である薬剤耐性癌に対する既存制癌剤の効
果増強剤の開発は非常に重要な新しい癌治療方法と考え
る。この臨床での制癌剤に対する耐性化の背景は、必ず
しも単純ではない、臨床における耐性には太き（分けて
２つの局面が考えられる。第一は個々の癌患者にその原
因が求められる場合であり、第二は癌細胞そのものに原
因かもとめられる場合である。近年この第二の場合にお
ける、耐性の機作が、分子レベルで解明されつつあり、
これに対する治療方法も検討されて米つつある。すなわ
ち、最近、多剤耐性を担う遺伝子が分離され、この遺伝
子は多剤耐性細胞に発現する膜蛋白質、ＰＩ膜蛋白質
Ｐ−ｇｌｙｃｏｐｒ。On the other hand, another important method is to try to enhance the effects of existing anticancer drugs. In particular, we believe that the development of agents that enhance the effects of existing anticancer drugs against drug-resistant cancer, which is a serious clinical problem in cancer treatment methods, is a very important new cancer treatment method. The background to this clinical resistance to anticancer drugs is not necessarily simple; there are two main aspects to clinical resistance.The first is when the cause is sought in individual cancer patients. The second case is when the cause is suspected to be in the cancer cells themselves.In recent years, the mechanism of resistance in this second case has been elucidated at the molecular level.
Treatment methods for this condition are also being studied. That is, a gene responsible for multidrug resistance has recently been isolated, and this gene is a membrane protein expressed in multidrug-resistant cells, PI membrane protein.
P-glycopr.
ｔｅｉｎ）の遺伝子であることが明らかとなった。Ｐ糖
蛋白質は制癌剤の細胞外排出の機能をもった蛋白質であ
る事が推定され、多剤耐性機構において中心的役割を担
う蛋白質であると考えられる。また、固型癌などの、も
ともと制癌剤の効きにくい癌にも一部共通の機作が示唆
されている。tein) gene. P-glycoprotein is presumed to be a protein that has the function of excreting anticancer drugs from cells, and is considered to be a protein that plays a central role in the multidrug resistance mechanism. In addition, some mechanisms have been suggested to be common to cancers that are inherently difficult to respond to anticancer drugs, such as solid cancers.
すなわち、多くの制癌剤は細胞膜を通過し、細胞内でそ
の効果を発現するか、耐性癌細胞においては、このＰ−
糖蛋白質の働きにより流入した制癌剤が細胞外へ排出さ
れ、癌細胞内の薬物濃度が低く保たれている。その結果
、制癌剤の効果が発現されにくいと考えられる。In other words, many anticancer drugs pass through the cell membrane and express their effects within the cell, or in resistant cancer cells, this P-
Due to the action of glycoproteins, the anticancer drug that has entered the body is expelled from the cell, keeping the concentration of the drug inside the cancer cell low. As a result, it is thought that the effects of anticancer drugs are less likely to be expressed.
よって１本発明者等は、例えばＰ−糖蛋白質の働きを抑
え、制癌剤の癌細胞からの流出を阻害する物質は、制癌
剤効果増強作用を有し、特に耐性の克服に有効であり、
新しい癌化学療法剤として成り得ると考える。Therefore, the present inventors believe that, for example, a substance that suppresses the action of P-glycoprotein and inhibits the outflow of anticancer drugs from cancer cells has an effect of enhancing the effect of anticancer drugs, and is particularly effective in overcoming resistance.
We believe that it can be used as a new cancer chemotherapeutic agent.
事実、部属等がベラバミール等のカルシウム拮抗剤が制
癌剤の癌細胞からの流出を阻止し、よって耐性癌に対し
、併用によってｉｎ ｖｉｔｒｏ ｉ３よびｉｎ ｖｉ
ｖｏでアドリアマイシン、ビンクリスチン等の制癌剤の
効果を増強させる作用を有する事を見出している。しか
し、これらカルシウム拮抗剤を臨床的に癌患者に使用す
る場合、血圧の低下、不整脈の誘発等の副作用が出現し
、癌治療剤としては大きな問題となっている。よって耐
性癌に対し、より強い制癌剤効果増強作用を有し、より
副作用の少ない薬剤が望まれていた。In fact, calcium antagonists such as berabamir block the outflow of anticancer drugs from cancer cells, and can therefore be used in combination against resistant cancers in vitro and in vitro.
It has been found that VO has the effect of enhancing the effects of anticancer drugs such as adriamycin and vincristine. However, when these calcium antagonists are used clinically in cancer patients, side effects such as a decrease in blood pressure and induction of arrhythmia appear, which poses a major problem as a cancer treatment agent. Therefore, there has been a desire for a drug that has a stronger effect of enhancing anticancer drug effects on resistant cancers and has fewer side effects.
一方２本発明の化合物は、例＾ば、特開昭６１−３７７
６５．５７−１４６７５４．５６−３２４５５等に記載
の公知化合物である。しかし、これら文献によれば、本
発明の化合物の薬理作用としては強心作用等の循環器に
関する記載が主で、癌に関する記載は全くない、まして
や、制癌剤効果増強作用については本発明者等が鋭意検
討した結果、見い出された作用である。On the other hand, two compounds of the present invention are disclosed in, for example, JP-A-61-377.
65.57-146754.56-32455 and the like. However, according to these documents, the pharmacological effects of the compound of the present invention are mainly described in relation to the circulatory system, such as cardiac inotropy, and there is no description in relation to cancer at all.In addition, the present inventors have made extensive efforts to investigate the effects of enhancing anticancer drug effects. This effect was discovered as a result of investigation.
〔課題を解決するための手段１
本発明δ等は、上記の観点に立ち、有効物質の探索に努
力し、特定のインドール誘導体が耐性癌において１強い
制癌剤効果増強作用を示す事を見い出し、本発明を完成
した。[Means for Solving the Problems 1] The present invention δ, etc., is based on the above-mentioned viewpoint, and has made efforts to search for effective substances, and has discovered that a specific indole derivative exhibits a strong anticancer drug effect enhancement effect on resistant cancer. Completed the invention.
すなわち１本発明は、一般式（Ｉ）
（式中、Ｒ２はメチル基、カルボキシル基、低級アルコ
キシカルボニル基、カルバモイル基またはシアノ基を示
し、Ｒ□、Ｒ１はる互いに独立してそれぞれ、フェニル
基、ピリジル基、チエニル基またはフリル基を示す、）
で表わされる化合物またはその塩を有効成分として含有
してなる制癌剤効果増強剤である。ここに低級アルコキ
シカルボニル基とは１例えば特にはメトキシカルボニル
基、エトキシカルボニル基等を示す。That is, 1 the present invention is based on the general formula (I) (wherein R2 represents a methyl group, a carboxyl group, a lower alkoxycarbonyl group, a carbamoyl group, or a cyano group, and R□ and R1 each independently represent a phenyl group). , pyridyl group, thienyl group, or furyl group) or a salt thereof as an active ingredient. The term "lower alkoxycarbonyl group" as used herein refers to, for example, a methoxycarbonyl group, an ethoxycarbonyl group, and the like.
また、本発明化合物のうち塩としては、塩酸、硫酸等の
無機酸または酢酸、蓚酸、マレイン酸、酒石酸等の有機
酸による塩が挙げられる。また、本発明化合物はその構
造の中に不斉炭素を有している為、光学異性体が存在す
るが、本発明化合物はこれらすべてを含有するものとす
る。Examples of the salts of the compounds of the present invention include salts with inorganic acids such as hydrochloric acid and sulfuric acid, or organic acids such as acetic acid, oxalic acid, maleic acid, and tartaric acid. Further, since the compound of the present invention has an asymmetric carbon in its structure, optical isomers exist, and the compound of the present invention is assumed to contain all of these.
次に本発明化合物の合成法であるが、β−プロ、／カー
作用薬として知られる３−アミノ−２−ヒドロキシ−プ
ロポキシアリール化合物の合成に用いられている通常の
方法により、容易に合成する事が出来る。すなわち、次
式で表わされる１
Ｈ（式中Ｒ，は前記と同じ、Ｘはハロゲ
ンを示す、）４−ヒドロキシインドール誘導体とエピク
ロルヒドリンまたはエビブロムヒドリンとを水酸化ナト
リウム、水素化ナトリウム、炭酸カリウム、ｔ−ブトキ
シカリウム、炭酸ナトリウム等の無機塩基、トリエチル
アミン、ピリジン等の有機塩基の存在下反応させ相当す
るエポキシ化合物へ誘導する・。溶媒としては、水溶媒
または、アルコール、アセトン、ＴＩ（Ｆ、ＤＭＦ等の
有機溶媒が使用でき、反応温度は０−１００℃の範囲が
好ましい。Next, regarding the method for synthesizing the compound of the present invention, it can be easily synthesized by a conventional method used for the synthesis of 3-amino-2-hydroxy-propoxyaryl compounds known as β-pro/car agonists. I can do things. In other words, 1 expressed by the following formula
H (in the formula, R is the same as above, X represents a halogen) 4-hydroxyindole derivative and epichlorohydrin or shrimp bromohydrin are combined with sodium hydroxide, sodium hydride, potassium carbonate, t-butoxypotassium, or sodium carbonate. The reaction is carried out in the presence of an inorganic base such as triethylamine, an organic base such as pyridine, etc., and the corresponding epoxy compound is derived. As the solvent, a water solvent or an organic solvent such as alcohol, acetone, TI(F, DMF, etc.) can be used, and the reaction temperature is preferably in the range of 0 to 100°C.
さらに相当するエポキシ化合物と相当するアミン誘導体
を熱的に反応させる事により本発明の一般式（Ｉ）の化
合物を得る事ができる。Furthermore, the compound of general formula (I) of the present invention can be obtained by thermally reacting a corresponding epoxy compound and a corresponding amine derivative.
■
本発明化合物の耐性癌に対する制癌剤効果増強作用は、
ヒト卵巣癌細胞のアドリアマイシン耐性株２７８０ＡＤ
または、ヒト骨髄性白血病細胞のアドリアマイシン耐性
株Ｋ ５６２／Ａ ＤＭを用い、その細胞内への制癌剤
保持増強効果および制癌剤の作用増強効果によって証明
される。■ The effect of enhancing the anticancer drug effect on resistant cancer of the compound of the present invention is
Adriamycin-resistant human ovarian cancer cell line 2780AD
Alternatively, the adriamycin-resistant strain K 562/A DM of human myeloid leukemia cells is used, and the evidence is demonstrated by the effect of enhancing the retention of the anticancer drug in the cells and the effect of enhancing the action of the anticancer drug.
本発明化合物は、試験例に詳しいが、いずれも、顕著な
制癌剤保持増強効果を示した。なかでも、４− （３−
（４−ジフェニルメチルビペラジン−１−イル）−２−
ヒドロキシプロポキシ＞−２−シアノ−ＩＨ−インドー
ルが強い効果を発現している。As detailed in the test examples, the compounds of the present invention all showed a remarkable effect of enhancing anticancer drug retention. Among them, 4- (3-
(4-diphenylmethylbiperazin-1-yl)-2-
Hydroxypropoxy>-2-cyano-IH-indole exhibits a strong effect.
また１本発明化合物又はその塩が併用される制癌剤とし
ては、特に制限はないが、好ましいものとしては非代謝
拮抗剤である、アンスラサイクリン系抗生物質１例えば
アドリアマイシン、タウノマイシン、アクラシノマイシ
ンＡ；アクチノマイシン系抗生物質１例えばアドリアマ
イシンＣ、アクチノマイシンＤ：クロモマイシン系抗生
物質、例えばミスラマイシン、トヨマイシン：ビンカア
ルカロイド、例＾ばビンクスチン、ビンブラスチン：メ
イタンシン類：ボドフィロトキシン誘導体、例えばＶＰ
ｌ ６−２１３ ；ホモハリントニン：アングウィデ
イン：プルセアンチン：ネオカルチノスタチン：アンス
ラマイシン、マイトマイシンＣ：シスプラチン誘導体等
である。There are no particular restrictions on the anticancer agent to which the compound of the present invention or a salt thereof is used, but preferred are non-antimetabolite antibiotics such as anthracycline antibiotics such as adriamycin, taunomycin, aclacinomycin A; Mycin antibiotics 1 such as adriamycin C, actinomycin D: chromomycin antibiotics such as mithramycin, toyomycin: vinca alkaloids such as vincustine, vinblastine: maytansines: bodophyllotoxin derivatives such as VP
l 6-213 ; Homohalintonin: Anguwidein: Purceantin: Neocarzinostatin: Anthramycin, Mitomycin C: Cisplatin derivatives, etc.
本発明化合物およびその塩の投与方法としては、制癌剤
の投与に際して、同時及びその前後に、制癌剤と配合ま
たは別々に投与する事が出来る。すなわち、本発明化合
物およびその塩は、単独で各種の投与法に準じた製剤と
し、各種の制癌剤と、それぞれ別個に投与することも出
来るが、両者を予め配合しておき、これ等を各種の投与
法に準じた製剤とした後に投与することもできる。The compounds of the present invention and their salts can be administered simultaneously with, before or after the anticancer drug, in combination with the anticancer drug, or separately. In other words, the compound of the present invention and its salt can be prepared alone in preparations according to various administration methods, and can be administered separately with various anticancer drugs. It can also be administered after making a preparation according to the administration method.
投与法としては、投与対象の症状、制癌剤の性状等によ
り当然異なるが、成人１日当たり１−１０００−ｇを１
回または数回に分割し１錠剤、顆粒剤、散剤、懸濁剤、
カプセル剤、シロップ剤等の経口投与剤、または注射剤
、座剤、輸液用等張液等の非経口投与剤として投与でき
る。The administration method varies depending on the symptoms of the subject, the properties of the anticancer drug, etc., but the dosage is 1-1000 g per day for adults.
One tablet, granules, powder, suspension, divided into one or several doses,
It can be administered orally, such as capsules and syrups, or parenterally, such as injections, suppositories, and isotonic solutions for infusion.
例えば錠剤とする場合、吸着剤としては結晶性セルロー
ス、軽質無水ケイ酸等を用い、賦形剤としてはトウモロ
コシデンプン、乳糖、燐酸カルシウム、ステアリン酸マ
グネシウム等が用いられる。また、注射剤とする場合、
化合物の水溶液または、綿実油、トウモロコシ油、ラッ
カセイ油、オリーブ油等を用いた懸濁性水溶液、さらに
はＨＣＯ−６０等の界面活性化剤等を用いた乳濁液とし
て使用される。なお、制癌剤の投与法は、各々の制癌剤
で選択されている各種の投与法をそのまま用いる事も出
来る。For example, in the case of tablets, crystalline cellulose, light anhydrous silicic acid, etc. are used as adsorbents, and corn starch, lactose, calcium phosphate, magnesium stearate, etc. are used as excipients. In addition, when used as an injection,
It is used as an aqueous solution of the compound, a suspension aqueous solution using cottonseed oil, corn oil, peanut oil, olive oil, etc., or an emulsion using a surfactant such as HCO-60. In addition, as for the administration method of the anticancer drug, various administration methods selected for each anticancer drug can be used as they are.
〔発明の効果］
本発明化合物は、制癌剤の癌細胞からの流出を強く阻害
し、しかも毒性が低く、血圧低下等の副作用が非常に少
ない特性を有する。[Effects of the Invention] The compounds of the present invention have the characteristics of strongly inhibiting the outflow of anticancer drugs from cancer cells, having low toxicity, and having very few side effects such as lowering of blood pressure.
したがって、本発明化合物は制癌剤に低感受性の癌細胞
や制癌剤への耐性を獲得した癌細胞に対して有効であり
、現在、行き詰まっている癌化学療法に新しい治療法を
提供しつるものである。Therefore, the compounds of the present invention are effective against cancer cells that are less sensitive to anticancer drugs and cancer cells that have acquired resistance to anticancer drugs, and provide a new treatment method for cancer chemotherapy, which is currently at a dead end.
以下に製造例および試験例を示すが、本発明はこれに限
定されるものではない。Production examples and test examples are shown below, but the present invention is not limited thereto.
製造例１
４− （３−（４−ジフェニルメチルビペラジン−１−
イル）−２−ヒドロキシプロポキシ）−２−シアノ−Ｉ
Ｈ−インドール
２−シアノ−４−ヒドロキシインドール２゜Ｏｇとエピ
クロルヒドリン２．０ｇおよび炭酸カリウム３．０ｇを
アセトン２０ｓβと混合し、６時間加熱還流した。不溶
物濾去後、溶媒を留去し、残渣をシリカゲルカラムクロ
マトグラフィーにて精製した。Production Example 1 4-(3-(4-diphenylmethylbiperazine-1-
yl)-2-hydroxypropoxy)-2-cyano-I
2.0 g of H-indole 2-cyano-4-hydroxyindole, 2.0 g of epichlorohydrin and 3.0 g of potassium carbonate were mixed with 20 sβ of acetone and heated under reflux for 6 hours. After removing the insoluble matter by filtration, the solvent was distilled off, and the residue was purified by silica gel column chromatography.
クロロホルム：メタノール＝１００ ： ｌで流出する
と目的物である２−シアノ−４−（２，３−エポキシ−
プロポキシ）−１日−インドールが１．６ｇ得られた。When chloroform:methanol=100:l flows out, the target product 2-cyano-4-(2,3-epoxy-
Propoxy) - 1 day - 1.6 g of indole was obtained.
これをエタノール５０−Ｑに溶解させ、さらにＮ−ジフ
ェニルメチルビペラジン２．０ｇを加え、２時間加熱還
流した。溶媒を減圧下留去し、残渣をシリカゲルカラム
クロマトグラフィーにて精製した。クロロホルム：メタ
ノール＝ １００：ｌで流出すると目的物である４−（
３−（４−ジフェニルメチルビペラジン−１−イル）−
２−ヒドロキシプロポキシ）−２−シアノ−ＩＨ−イン
ドールが２．１ｇ得られた。This was dissolved in ethanol 50-Q, 2.0 g of N-diphenylmethylbiperazine was added, and the mixture was heated under reflux for 2 hours. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography. The target product 4-(
3-(4-diphenylmethylbiperazin-1-yl)-
2.1 g of 2-hydroxypropoxy)-2-cyano-IH-indole was obtained.
ｍ ｐ、 １６２〜１６３．５℃
試験例１．薬剤耐性癌細胞内での抗癌剤保持増強効果
ヒト卵巣癌細胞Ａ２７８０のアドリアマイシン耐性株２
７８０ Ａ Ｄ ＩＡ、Ｍ、Ｒｏｇａｎら、 ５ｃｉｅ
ｎｃｅ、 ２２４巻、 ９９４−９９６頁、 １９８４
年）を５％牛脂児血清を含むＲＰＭＩ−１６４０培養液
中ニ１ＸｌＯ’個／ｌｓ９！Ｑｉ’ｌＪＬ、直径１６ｃ
ｍ、２４穴の？ＪＬ、チウエル培養プレートに１穴あた
り ｌ ＠ｌの癌細胞懸濁液を播種し、５％ＣＯｇ、
３７℃で培養した。２４時間後に培養液を２０ ｎＭ
３Ｈ−ビンクリスチン（Ｉ Ｘ ｌＯ’ｄｐｍ／ｐｉ＋
ｏｌ） 、 ５％牛脂児血清、１０ ｎＭへベス緩衝液
を含むＲＰＭＩ−１６４０培養液０．５−βと交換した
。ＤＭＳＯに溶解した後、生理リン酸緩衝液で希釈した
被験化合物を５μβ加え（反応液中濃度はｉ、ｏまたは
１０．０μｇ／−２）、５％ＣＯｉ、 ３７℃で２時間
培養を続けた後、細胞を冷却した生理リン酸緩衝液で洗
浄した。これを０．５−βの０．２ Ｎ−ＮａＯＨを加
え、バイアルに移し、５６℃で３０〜６０分間温浴し、
細胞を溶解させた。アシッド・アクアゾール２を４■β
加え、液体シンチレーションカウンターで細胞内の３Ｈ
−ビンクリスチンの量を測定した。m p, 162-163.5°C Test Example 1. Effect of enhancing anticancer drug retention in drug-resistant cancer cells Adriamycin-resistant strain 2 of human ovarian cancer cell A2780
780 AD IA, M., Logan et al., 5cie
nce, vol. 224, pp. 994-996, 1984
) in RPMI-1640 culture medium containing 5% tallow serum. Qi'lJL, diameter 16c
M, 24 holes? JL, Chiwell culture plate was seeded with 1 @ 1 cancer cell suspension per well, 5% COg,
Cultured at 37°C. After 24 hours, culture medium was diluted with 20 nM
3H-vincristine (I X lO'dpm/pi+
ol) was replaced with RPMI-1640 medium 0.5-β containing 5% tallow serum, 10 nM Heves buffer. After dissolving in DMSO, 5 μβ of the test compound diluted with physiological phosphate buffer was added (concentration in the reaction solution was i, o, or 10.0 μg/−2), and culture was continued for 2 hours at 37°C in 5% COi. Afterwards, the cells were washed with cold physiological phosphate buffer. Add 0.5-β of 0.2 N-NaOH to this, transfer to a vial, and bathe at 56°C for 30 to 60 minutes.
Cells were lysed. Acid Aquasol 2 4■β
In addition, intracellular 3H was detected using a liquid scintillation counter.
- The amount of vincristine was determined.
効果は薬物無処理の対照群に保持されていたビンクリス
チンの量をｌＯＯとして、薬物処理群に取り込まれたビ
ンクリスチンの量を百分率（％）で表わした１代表化合
物として製造例１で示した化合物の結果を表１に示した
。The effect of the compound shown in Production Example 1 is expressed as 1 representative compound, where the amount of vincristine retained in the drug-free control group is expressed as lOO, and the amount of vincristine taken up in the drug-treated group is expressed as a percentage (%). The results are shown in Table 1.
表１ 特許出願人 財団法人 癌研究会 特許出願人 三井東圧化学株式会社 ４（理人？纂マを后朴 、吃・Table 1 Patent applicant Cancer Research Foundation Patent applicant: Mitsui Toatsu Chemical Co., Ltd. 4.
Claims (1)
コキシカルボニル基、カルバモイル基またはシアノ基を
示し、Ｒ＿２、Ｒ＿３はお互いに独立してそれぞれ、フ
ェニル基、ピリジル基、チエニル基またはフリル基を示
す。） で表わされる化合物またはその塩を有効成分として含有
してなる制癌剤効果増強剤。 ２、式 ▲数式、化学式、表等があります▼ で表わされる化合物またはその塩を有効成分として含有
してなる制癌剤効果増強剤。[Claims] 1. General formula (I) ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (I) (In the formula, R_1 represents a methyl group, a carboxyl group, a lower alkoxycarbonyl group, a carbamoyl group, or a cyano group. , R_2, and R_3 each independently represent a phenyl group, a pyridyl group, a thienyl group, or a furyl group. 2. An anticancer drug effect enhancer containing a compound represented by the formula ▲There are mathematical formulas, chemical formulas, tables, etc.▼ or a salt thereof as an active ingredient.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP27445088A JPH02121924A (en) | 1988-11-01 | 1988-11-01 | Carcinostatic agent effect-enhancing agent |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP27445088A JPH02121924A (en) | 1988-11-01 | 1988-11-01 | Carcinostatic agent effect-enhancing agent |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH02121924A true JPH02121924A (en) | 1990-05-09 |
| JPH0565487B2 JPH0565487B2 (en) | 1993-09-17 |
Family
ID=17541861
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP27445088A Granted JPH02121924A (en) | 1988-11-01 | 1988-11-01 | Carcinostatic agent effect-enhancing agent |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH02121924A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1994022846A1 (en) * | 1993-03-30 | 1994-10-13 | Pfizer Inc. | Compounds enhancing antitumor activity of other cytotoxic agents |
| US6130217A (en) * | 1995-09-20 | 2000-10-10 | Pfizer Inc | Compounds enhancing antitumor activity of other cytotoxic agents |
-
1988
- 1988-11-01 JP JP27445088A patent/JPH02121924A/en active Granted
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1994022846A1 (en) * | 1993-03-30 | 1994-10-13 | Pfizer Inc. | Compounds enhancing antitumor activity of other cytotoxic agents |
| US6130217A (en) * | 1995-09-20 | 2000-10-10 | Pfizer Inc | Compounds enhancing antitumor activity of other cytotoxic agents |
Also Published As
| Publication number | Publication date |
|---|---|
| JPH0565487B2 (en) | 1993-09-17 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| WO2021073439A1 (en) | Pyrazine derivative for inhibiting shp2 activity | |
| CN105189456B (en) | KRAS G12C covalency inhibitor | |
| CN106170288B (en) | Medical compounds | |
| CN105693624B (en) | Macitentan crystal and preparation method thereof, its pharmaceutical composition and purposes | |
| HUE031999T2 (en) | Cyclic n,n'-diarylthioureas and n,n'-diarylureas as androgen receptor antagonists, anti-cancer agent, method for producing and using same | |
| WO2023165165A1 (en) | Benzoimidazopyrazine-3-carboxamide compound targeting a2a and anti-tumor immunological function thereof | |
| CN107108580A (en) | Oxindole compounds and application thereof | |
| CN107438598A (en) | Quinazoline and quinoline compound and application thereof | |
| CN108349946A (en) | Quinoxaline and pyrido-pyrazine derivatives as PI3K beta inhibitors | |
| CN110028509B (en) | Pyrrolopyrimidines as selective JAK2 inhibitors, and synthesis method and application thereof | |
| WO2023078451A1 (en) | Compound used as cdk7 kinase inhibitor and use thereof | |
| WO2020238776A1 (en) | Substituted fused bicyclic derivative, preparation method therefor, and application thereof in medicines | |
| TWI822666B (en) | Crystalline forms of a janus kinase inhibitor | |
| AU2013318672A1 (en) | Means and method for treating solid tumours | |
| CN110903283A (en) | Substituted quinazoline compound, pharmaceutical composition containing compound and application of compound | |
| CN107207476A (en) | Indoles and 7-azaindole derivatives and its for the purposes in neurodegenerative disorders | |
| US8344017B2 (en) | Anti-hepatitis C virus agents and anti-HIV agents | |
| JP3076672B2 (en) | Fumarate of quinoline derivative | |
| JPH02121924A (en) | Carcinostatic agent effect-enhancing agent | |
| WO2019001307A1 (en) | Amide compound, composition containing same, and use thereof | |
| WO2021057867A1 (en) | Class of cdk inhibitor based on organic arsine, preparation method and application thereof | |
| EP0648491A2 (en) | Eosinophil chemotaxis inhibitor | |
| CN105636956A (en) | Indole compound as inhibitor of necrosis | |
| JP2781073B2 (en) | Novel quinoline derivative and anticancer drug effect enhancer containing the same as active ingredient | |
| WO2023006057A1 (en) | Crystal of amino pyrazolopyrimidine compound |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20080917 Year of fee payment: 15 |
|
| FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20080917 Year of fee payment: 15 |
|
| FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20090917 Year of fee payment: 16 |
|
| EXPY | Cancellation because of completion of term | ||
| FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20090917 Year of fee payment: 16 |