JPH04356466A - New quinoline derivative and carcinostatic agent effect enhancer containing the derivative as active ingredient - Google Patents
New quinoline derivative and carcinostatic agent effect enhancer containing the derivative as active ingredientInfo
- Publication number
- JPH04356466A JPH04356466A JP2508291A JP2508291A JPH04356466A JP H04356466 A JPH04356466 A JP H04356466A JP 2508291 A JP2508291 A JP 2508291A JP 2508291 A JP2508291 A JP 2508291A JP H04356466 A JPH04356466 A JP H04356466A
- Authority
- JP
- Japan
- Prior art keywords
- formula
- compound
- general formula
- quinoline
- anticancer drug
- 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.)
- Pending
Links
- 239000004480 active ingredient Substances 0.000 title claims abstract description 5
- 239000003623 enhancer Substances 0.000 title claims description 8
- 230000000694 effects Effects 0.000 title abstract description 28
- 239000003795 chemical substances by application Substances 0.000 title abstract description 4
- 230000003327 cancerostatic effect Effects 0.000 title abstract 2
- 125000002943 quinolinyl group Chemical class N1=C(C=CC2=CC=CC=C12)* 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 36
- MMRYHBTWIHLITG-UHFFFAOYSA-N 5-(oxiran-2-ylmethoxy)quinoline Chemical compound C=1C=CC2=NC=CC=C2C=1OCC1CO1 MMRYHBTWIHLITG-UHFFFAOYSA-N 0.000 claims abstract description 4
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 4
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 4
- 238000002347 injection Methods 0.000 claims abstract description 4
- 239000007924 injection Substances 0.000 claims abstract description 4
- 239000000725 suspension Substances 0.000 claims abstract description 4
- 150000001412 amines Chemical class 0.000 claims abstract description 3
- 239000002775 capsule Substances 0.000 claims abstract description 3
- 239000008187 granular material Substances 0.000 claims abstract description 3
- 239000000644 isotonic solution Substances 0.000 claims abstract description 3
- 239000000843 powder Substances 0.000 claims abstract description 3
- 239000000829 suppository Substances 0.000 claims abstract description 3
- 239000006188 syrup Substances 0.000 claims abstract description 3
- 235000020357 syrup Nutrition 0.000 claims abstract description 3
- 239000003826 tablet Substances 0.000 claims abstract description 3
- 239000003995 emulsifying agent Substances 0.000 claims abstract 2
- 239000002246 antineoplastic agent Substances 0.000 claims description 46
- 229940041181 antineoplastic drug Drugs 0.000 claims description 44
- 238000000034 method Methods 0.000 claims description 14
- 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 claims description 11
- 230000000857 drug effect Effects 0.000 claims description 11
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims description 8
- 150000003839 salts Chemical class 0.000 claims description 8
- 229960004528 vincristine Drugs 0.000 claims description 7
- 229940009456 adriamycin Drugs 0.000 claims description 5
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical group 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 claims description 5
- 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 claims description 5
- 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 claims description 4
- FWJPNVOQWGVWFU-UHFFFAOYSA-N [4-(2-hydroxy-3-quinolin-5-yloxypropyl)piperazin-1-yl]-(9h-xanthen-9-yl)methanone Chemical compound C12=CC=CC=C2OC2=CC=CC=C2C1C(=O)N(CC1)CCN1CC(O)COC1=CC=CC2=NC=CC=C12 FWJPNVOQWGVWFU-UHFFFAOYSA-N 0.000 claims description 3
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- 125000005843 halogen group Chemical group 0.000 claims description 3
- 238000001802 infusion Methods 0.000 claims description 2
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- VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 claims 1
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- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 abstract description 9
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- 231100000053 low toxicity Toxicity 0.000 abstract description 3
- PLKYUVMSQZFXNQ-UHFFFAOYSA-N 9h-fluoren-9-yl-[4-(2-hydroxy-3-quinolin-5-yloxypropyl)piperazin-1-yl]methanone Chemical compound C12=CC=CC=C2C2=CC=CC=C2C1C(=O)N(CC1)CCN1CC(O)COC1=CC=CC2=NC=CC=C12 PLKYUVMSQZFXNQ-UHFFFAOYSA-N 0.000 abstract description 2
- 238000009835 boiling Methods 0.000 abstract description 2
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- 150000002367 halogens Chemical class 0.000 abstract 1
- 206010028980 Neoplasm Diseases 0.000 description 23
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- 210000004027 cell Anatomy 0.000 description 20
- -1 5-[3-{4-(10,11-dihydro-5 H-dibenzo[b,f]azepine-5-carbonyl)piperazin-1-yl}-2-hydroxypropoxy]quinoline Chemical compound 0.000 description 12
- GLUUGHFHXGJENI-UHFFFAOYSA-N diethylenediamine Natural products C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 10
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- IRQXZTBHNKVIRL-AYXPYFKUSA-N bruceantin Natural products CC1=C(O)C(=O)C[C@]2(C)[C@@H]([C@@H](O)[C@@H]3O)[C@@]45CO[C@@]3(C(=O)OC)[C@@H]5[C@@H](OC(=O)C=C(C)C(C)C)C(=O)O[C@@H]4C[C@H]21 IRQXZTBHNKVIRL-AYXPYFKUSA-N 0.000 description 1
- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 108700002839 cactinomycin Proteins 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
- 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
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 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
- 238000001816 cooling 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
- 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 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
- 238000001035 drying Methods 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- DKAGJZJALZXOOV-UHFFFAOYSA-N hydrate;hydrochloride Chemical compound O.Cl DKAGJZJALZXOOV-UHFFFAOYSA-N 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 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
- 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
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 238000007911 parenteral administration Methods 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
- 229960003171 plicamycin Drugs 0.000 description 1
- YJGVMLPVUAXIQN-XVVDYKMHSA-N podophyllotoxin Chemical class COC1=C(OC)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@H](O)[C@@H]3[C@@H]2C(OC3)=O)=C1 YJGVMLPVUAXIQN-XVVDYKMHSA-N 0.000 description 1
- 239000003600 podophyllotoxin derivative Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 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
- 239000011734 sodium Substances 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- XHFLOLLMZOTPSM-UHFFFAOYSA-M sodium;hydrogen carbonate;hydrate Chemical class [OH-].[Na+].OC(O)=O XHFLOLLMZOTPSM-UHFFFAOYSA-M 0.000 description 1
- 239000007787 solid 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
- 238000001308 synthesis method Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 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
- 229950009268 zinostatin Drugs 0.000 description 1
Abstract
Description
【0001】0001
【産業上の利用分野】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。TECHNICAL FIELD The present invention relates to a novel compound and an anticancer drug effect enhancer containing the same as an active ingredient.
【0002】0002
【従来の技術】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一位を占め、社会的に癌の治療に対
する関心は高い。BACKGROUND OF THE INVENTION 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 level of social interest in cancer treatment.
【0003】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、多くの場合、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
満足出来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。[0003] Research and development of anticancer drugs for the treatment of cancer has been actively conducted for a long time, and various anticancer drugs are used clinically for the treatment of cancer. Although its effectiveness is steadily improving over the years, in many cases it completely suppresses cancer growth;
A satisfactory effect in maintaining the survival of cancer patients over a long period of time has not necessarily been achieved. Furthermore, many attempts are currently being made clinically to enhance the effects of anticancer drugs by combining multiple anticancer drugs (multidrug combination therapy). However, this case is also unsatisfactory as a chemotherapy method for cancer, and there is a strong need for the development of new cancer therapeutics from a new perspective.
【0004】このような事情において、一つの方法とし
ては、一層強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。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、癌化学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られる。
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大きく分けて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が
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来つつある。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、P糖蛋白質(p−gly
coprotein)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。[0004] Under these circumstances, one possible method would be to develop more powerful anticancer drugs and to develop a method for more selectively transporting anticancer drugs to target organs. the current,
These studies are being carried out all over the world, but the current situation is that they are becoming increasingly difficult. On the other hand, another important method is to try to enhance the effects of existing anticancer drugs. In particular, the development of agents that enhance the effects of existing anticancer drugs against drug-resistant cancer, which is a serious clinical problem in cancer chemotherapy, is considered to be a very important new cancer treatment method. The background of clinical resistance to anticancer drugs is not necessarily simple. Resistance in clinical practice can be broadly divided into two aspects. The first is when the cause is sought in an individual cancer patient, and the second is when the cause is sought in the cancer cells themselves. In recent years, the mechanism of resistance in this second case has been elucidated at the molecular level, and treatment methods for this are also being investigated. Specifically, a gene responsible for multidrug resistance has recently been isolated, and this gene is responsible for the membrane protein P-glycoprotein (p-gly) expressed in multidrug-resistant cells.
It was revealed that the gene is a gene of coprotein. 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. Furthermore, some mechanisms have been suggested to be common to cancers such as solid cancers, which are inherently difficult to respond to anticancer drugs.
【0005】すなわち、多くの制癌剤の細胞膜を通過し
、細胞内でその効果を発現するが、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。That is, many anticancer drugs pass through the cell membrane and express their effects within the cell, but in resistant cancer cells, the inflowing anticancer drugs are excreted outside the cells by the action of this P-glycoprotein, and the cancer cells The drug concentration in the blood is kept low. As a result, it is thought that the effects of anticancer drugs are less likely to be expressed.
【0006】よって、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。[0006] Therefore, the present inventors believe that a substance that suppresses the action of P-glycoprotein and inhibits the outflow of anticancer drugs from cancer cells has the 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.
【0007】事実、鶴尾等はベラパルミール等のカルシ
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およびi
n vitroでアドリアマシイン、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, Tsuruo et al. have shown that calcium antagonists such as verapalmil block the outflow of anticancer drugs from cancer cells, and therefore can be used in combination against resistant cancers in vitro and i.
It has been found that it has the effect of enhancing the effects of anticancer drugs such as adriamasin and vincristine in vitro. 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.
【0008】[0008]
【発明が解決しようとする課題】本発明の目的は耐性癌
に対しより強い制癌剤効果増強作用を有し、より副作用
の少ない薬剤を提供することである。SUMMARY OF THE INVENTION An object of the present invention is to provide a drug that has a stronger effect of enhancing anticancer drug effects on resistant cancers and has fewer side effects.
【0009】[0009]
【課題を解決するための手段】本発明者等は、上記の観
点に鑑み鋭意検討した結果、特定の化合物が耐性癌に対
し、強い制癌剤効果増強作用を示し、かつ低毒性・低副
作用を有する事を見出し、本発明を完成した。すなわち
、本発明は、一般式(1)[Means for Solving the Problems] As a result of intensive studies in view of the above points, the present inventors have found that a specific compound exhibits a strong effect of enhancing anticancer drug effects against resistant cancers, and has low toxicity and low side effects. They discovered this and completed the present invention. That is, the present invention provides general formula (1)
【0010】0010
【化4】[C4]
【0011】[0011]
【化5】
ここでR1 はハロゲン原子、低級アルキル基、低級ア
ルコキシ基を表わす。)で表わされる化合物及びその塩
(以下、本発明化合物という。)、それらを有効成分と
して含有する制癌剤効果増強剤およびそれらを製造する
方法である。embedded image Here, R1 represents a halogen atom, a lower alkyl group, or a lower alkoxy group. ) and their salts (hereinafter referred to as compounds of the present invention), anticancer drug effect enhancers containing them as active ingredients, and methods for producing them.
【0012】ここで挙げているハロゲン原子とは、フッ
素原子、塩素原子、臭素原子などを意味する。また、低
級アルキル基とは、メチル基、エチル基、プロピル基、
ブチル基などを意味する。また、低級アルコキシ基とは
、メトキシ基、エトキシ基、プロポキシ基、ブトキシ基
などを意味する。The halogen atom mentioned here means a fluorine atom, a chlorine atom, a bromine atom, etc. In addition, lower alkyl groups include methyl group, ethyl group, propyl group,
It means a butyl group, etc. Further, the lower alkoxy group means a methoxy group, an ethoxy group, a propoxy group, a butoxy group, and the like.
【0013】また、本発明化合のうち塩としては、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。好ましい化合物としては次のものを挙げ
ることができる。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. Preferred compounds include the following.
【0014】[0014]
【化6】
(式中R1は一般式(1)と同じ意味を表わす。)5−
〔3−{4−(フルオレン−9−カルボニル)ピペラジ
ン−1−イル}−2−ヒドロキシプロポキシ〕キノリン
、5−〔3−{4−(キサンテン−9−カルボニル)ピ
ペラジン−1−イル}−2−ヒドロキシプロポキシ〕キ
ノリン、5−〔3−{4−(10,11−ジヒドロ−5
H−ジベンゾ〔b,f〕アゼピン−5−カルボニル)ピ
ペラジン−1−イル}−2−ヒドロキシプロポキシ〕キ
ノリン。[Chemical formula 6] (In the formula, R1 represents the same meaning as in general formula (1).) 5-
[3-{4-(fluorene-9-carbonyl)piperazin-1-yl}-2-hydroxypropoxy]quinoline, 5-[3-{4-(xanthene-9-carbonyl)piperazin-1-yl}-2 -hydroxypropoxy]quinoline, 5-[3-{4-(10,11-dihydro-5
H-dibenzo[b,f]azepine-5-carbonyl)piperazin-1-yl}-2-hydroxypropoxy]quinoline.
【0015】次に本発明の合成法であるが、次式に表わ
される5−(2,3−エポキシプロポキシ)キノリンと
相当するアミン誘導体を熱的、あるいは塩基存在下反応
させ本発明の一般式(1)の化合物を得る事ができる。Next, in the synthesis method of the present invention, 5-(2,3-epoxypropoxy)quinoline represented by the following formula and a corresponding amine derivative are reacted thermally or in the presence of a base to obtain the general formula of the present invention. Compound (1) can be obtained.
【0016】[0016]
【化7】
ここに熱的とは室温から溶媒の沸点までを意味し、溶媒
としてはアルコール、アセトン、クロロホルム、塩化メ
チレン、ジメチルホルムアミド等の有機溶媒が使用され
る。また、塩基としては、炭酸カリウム、水酸化ナトリ
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、ジアザビシクロウンデセン等の有機塩基を
表わす。embedded image Here, thermal means from room temperature to the boiling point of the solvent, and organic solvents such as alcohol, acetone, chloroform, methylene chloride, and dimethylformamide are used as the solvent. Further, examples of the base include inorganic bases such as potassium carbonate, sodium hydroxide and sodium carbonate, and organic bases such as triethylamine, pyridine and diazabicycloundecene.
【0017】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K562/ADMを用い、その細胞内へ
の制癌剤取り込み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。すなわち、本発明化合物は、実施
例で詳しく述べるが、いずれも顕著な制癌剤取り込み増
強効果および制癌剤作用増強効果を示した。[0017] The anticancer drug effect enhancement effect of the compound of the present invention against resistant cancer can be achieved by enhancing the uptake of the anticancer drug into the cells using the adriamycin-resistant human ovarian cancer cell line 2780AD or the adriamycin-resistant line K562/ADM of human myeloid leukemia cells. This is evidenced by its effectiveness and the effect of enhancing the action of anticancer drugs. That is, as will be described in detail in the Examples, the compounds of the present invention all exhibited significant anticancer drug uptake enhancement effects and anticancer drug action enhancement effects.
【0018】また、本発明化合物又はその塩と併用する
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
、例えばアドリアマイシン、ダウノマイシン、アクラシ
ノマイシンA;アクチノマイシン系抗生物質、例えばア
クチノマイシン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、例えばビンクリスチン、ビンブラ
スチン;メイタンシン類;ポドフィロトキシン誘導体、
例えばVP16−213;ホモハリントニン;アングウ
ィデイン;ブルセアンチン;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。[0018] Anticancer agents to be used in combination with the compound of the present invention or a salt thereof are not particularly limited, but preferred are non-antimetabolite anthracycline antibiotics such as adriamycin, daunomycin, aclacinomycin A; Actinomycin antibiotics, such as actinomycin C, actinomycin D; chromomycin antibiotics, such as mithramycin, toyomycin;
Vinca alkaloids, such as vincristine, vinblastine; maytansines; podophyllotoxin derivatives,
For example, VP16-213; homohalintonin; anguwidein; bruceantin; neocarzinostatin; anthramycin; mitomycin C; cisplatin derivatives and the like.
【0019】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。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人当たり1〜1000mg
を1回または数回に分割し、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 compound of the present invention and its salts can be administered simultaneously with, before or after the anticancer drug, in combination with the anticancer drug, or separately. That is,
The compounds of the present invention and their salts can be prepared alone in preparations according to various administration methods, and can be administered separately with various anticancer drugs, but they can be mixed in advance and used in various administration methods. It can also be administered after being made into a similar formulation. The administration method varies depending on the symptoms of the subject, the properties of the anticancer drug, etc., but the dose is 1 to 1000 mg per adult.
divided into one or several doses and used for oral administration such as tablets, granules, powders, suspensions, capsules, and syrups, or for parenteral administration such as injections, suppositories, and isotonic solutions for infusion. It can be administered as
【0020】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
用いる事が出来る。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. When preparing an injection, the compound may be prepared as an aqueous solution, a suspension aqueous solution using cottonseed oil, corn oil, peanut oil, olive oil, etc., or an emulsion using a surfactant such as HCO-60. used. The administration method for anticancer drugs is as follows:
Various administration methods selected for each anticancer drug can be used as they are.
【0021】[0021]
【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 strongly inhibit the outflow of anticancer drugs from cancer cells, have low toxicity, and have very few side effects such as lowering of blood pressure.
【0022】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うるものである。Therefore, the compound of the present invention is effective against cancer cells that are less sensitive to anticancer drugs and cancer cells that have acquired resistance to anticancer drugs, and may provide a new treatment method for cancer chemotherapy, which is currently at a dead end. It is.
【0023】[0023]
【実施例】以下に本発明を実施例にて示すが、本発明は
これに限定されるものではない。
実施例1
5−〔3−{4−(α,α−ビス(4−メトキシフェニ
ル)アセチル)ピペラジン−1−イル}−2−ヒドロキ
シプロポキシ〕キノリン
a)α,α−ビス(4−メトキシフェニル)酢酸2.5
gを塩化チオニル3.56gに加え6時間加熱還流を行
った。ついで過剰の塩化チオニルを減圧留去し、α,α
−ビス(4−メトキシフェニル)酢酸クロリドの粗生成
物を2.8g得た。NMR δppm(CDCl3)
:3.75(s,1H)、5.30(s,1H)、6.
73〜6.9(m,4H)、7.08〜7.38(m,
4H)b)N−ホルミルピペラジン1.27gとトリエ
チルアミン1.58mlをクロロホルム7mlに加えた
。ついで、上記合成の酸クロリド2.8gのクロロホル
ム5ml溶液を水冷下滴下し、室温で1夜放置した。さ
らに、0.3NHCl水を加え、クロロホルムで抽出し
、飽和NaHCO3水で2回洗浄し、乾燥・濃縮し、4
−{α,α−ビス(4−メトキシフェニル)アセチル}
−1−ホルミルピペラジンの粗生成物を3.5g得た。
NMR δppm(CDCl3):3.44〜3.5
3(m,4H)、3.67〜3.74(m,4H)、3
.78(s,6H)、5.09(s,1H)、6.84
(d,4H)、7.11(d,4H)
c)上記合成により得られたホルミルピペラジン体3.
5gをCHCl3 10mlに溶解し、12%HCl/
MeOH溶液を15ml加えた。1夜放置し、飽和Na
HCO3水を加え、CHCl3 で抽出し、乾燥・濃縮
し残渣をシリカゲルカラムで精製(CHCl3 :Me
OH=25:1)し、N−{α,α−ビス(4−メトキ
シフェニル)アセチル}ピペラジンを1.65g得た。
NMR δppm(CDCl3):2.5〜2.8(
m,4H)、3.3〜3.6(m,4H)、3.70(
s,6H)、4.98(s,1H)、6.62〜7.2
0(m,8H)
d)上記によって合成されたピペラジン体1.60gと
5−(2,3−エポキシプロポキシ)キノリン1.12
gをエタノール15.6ml中に溶解し、3時間加熱還
流した。溶媒を減圧留去し残渣をシリカゲルカラム(C
HCl3 :MeOH=アンモニア水=500:10:
1)で精製し、表記化合物を1.86g得た。
NMR δppm(CDCl3):2.17〜2.2
2(m,1H)、2.43〜2.48(m,2H)、2
.59〜2.69(m,3H)、3.49(br.s,
1H)、3.47〜3.51(m,2H)、3.73〜
3.78(m,2H)、4.13〜4.24(m,3H
)、5.09(s,1H)、6.85(m,1H)、7
.1(m,3H)、7.36(m,1H)、7.60(
m,1H)、7.71(m,1H)、8.54(m,1
H)、8.90(m,1H)
IR νcm−1(neat):3401、2934
、1644、1510、1463、1249、1177
、1096、1033、800、754[Examples] The present invention will be illustrated below with examples, but the present invention is not limited thereto. Example 1 5-[3-{4-(α,α-bis(4-methoxyphenyl)acetyl)piperazin-1-yl}-2-hydroxypropoxy]quinoline a) α,α-bis(4-methoxyphenyl ) acetic acid 2.5
g was added to 3.56 g of thionyl chloride and heated under reflux for 6 hours. Then, excess thionyl chloride was distilled off under reduced pressure, and α, α
2.8 g of a crude product of -bis(4-methoxyphenyl)acetic acid chloride was obtained. NMR δppm (CDCl3)
:3.75 (s, 1H), 5.30 (s, 1H), 6.
73-6.9 (m, 4H), 7.08-7.38 (m,
4H) b) 1.27 g of N-formylpiperazine and 1.58 ml of triethylamine were added to 7 ml of chloroform. Then, a solution of 2.8 g of the acid chloride synthesized above in 5 ml of chloroform was added dropwise under water cooling, and the mixture was left to stand overnight at room temperature. Furthermore, 0.3N HCl water was added, extracted with chloroform, washed twice with saturated NaHCO3 water, dried and concentrated, and
-{α,α-bis(4-methoxyphenyl)acetyl}
3.5 g of crude product of -1-formylpiperazine was obtained. NMR δppm (CDCl3): 3.44-3.5
3 (m, 4H), 3.67-3.74 (m, 4H), 3
.. 78 (s, 6H), 5.09 (s, 1H), 6.84
(d,4H), 7.11(d,4H) c) Formylpiperazine compound obtained by the above synthesis 3.
Dissolve 5g in 10ml of CHCl3 and add 12% HCl/
15 ml of MeOH solution was added. Leave it overnight and add saturated Na
HCO3 water was added, extracted with CHCl3, dried and concentrated, and the residue was purified with a silica gel column (CHCl3:Me
OH=25:1) to obtain 1.65 g of N-{α,α-bis(4-methoxyphenyl)acetyl}piperazine. NMR δppm (CDCl3): 2.5-2.8 (
m, 4H), 3.3-3.6 (m, 4H), 3.70 (
s, 6H), 4.98 (s, 1H), 6.62-7.2
0(m,8H) d) 1.60 g of the piperazine compound synthesized above and 1.12 g of 5-(2,3-epoxypropoxy)quinoline
g was dissolved in 15.6 ml of ethanol and heated under reflux for 3 hours. The solvent was distilled off under reduced pressure and the residue was filtered through a silica gel column (C
HCl3:MeOH=ammonia water=500:10:
1) to obtain 1.86 g of the title compound. NMR δppm (CDCl3): 2.17-2.2
2 (m, 1H), 2.43-2.48 (m, 2H), 2
.. 59-2.69 (m, 3H), 3.49 (br.s,
1H), 3.47~3.51 (m, 2H), 3.73~
3.78 (m, 2H), 4.13-4.24 (m, 3H
), 5.09 (s, 1H), 6.85 (m, 1H), 7
.. 1 (m, 3H), 7.36 (m, 1H), 7.60 (
m, 1H), 7.71 (m, 1H), 8.54 (m, 1H)
H), 8.90 (m, 1H) IR νcm-1 (neat): 3401, 2934
, 1644, 1510, 1463, 1249, 1177
, 1096, 1033, 800, 754
【0024】実施例2
5−〔3−{4−(キサンテン−9−カルボニル)ピペ
ラジン−1−イル}−2−ヒドロキシプロポキシ〕キノ
リン
a)キサンテン−9−カルボン酸2.44gを用いて実
施例1−a)に従って反応し、キサンテン−9−カルボ
ン酸クロライドの粗生成物を2.62g得た。
NMR δppm(CDCl3):5.35(s,1
H)、7.06〜7.30(m,8H)
b)上記合成の酸クロリド2.62gを用いて実施例1
−b)に従って反応し、1−ホルミル−4−(キサンテ
ン−9−カルボニル)ピペラジンの粗生成物を3.91
g得た。
NMR δppm(CDCl3):2.94〜3.8
0(m,8H)、5.45(s,1H)、6.97〜7
.25(m,8H)、7.84(s,1H)c)上記に
よって合成されたホルミルピペラジン体3.91gを用
いて実施例1−c)に従って反応し、N−(キサンテン
−9−カルボニル)ピペラジン2.38g得た。
m.p.146.1〜147.5℃
NMR δppm(CDCl3):2.20〜2.8
0(m,4H)、3.00〜3.50(m,4H)、5
.35(s,1H)、6.90〜7.2(m,8H)d
)上記によって合成されたピペラジン体1.03gを用
いて実施例1−d)に従って反応し、表記化合物を0.
876g得た。
NMR δppm(CDCl3):1.97(br.
s,1H)、2.17(br.s,1H)、2.47〜
2.63(m,4H)、3.28〜3.33(m,2H
)、3.69〜3.73(m,2H)、4.07〜4.
17(m,3H)、5.46(s,1H)、6.8〜7
.7(m,8H)、8.52(d,1H)、8.90(
dd,1H)
IR νcm−1(KBr):3188、2933、
1630、1579、1457、1260、795、7
20Example 2 5-[3-{4-(xanthene-9-carbonyl)piperazin-1-yl}-2-hydroxypropoxy]quinoline a) Example using 2.44 g of xanthene-9-carboxylic acid The reaction was carried out according to 1-a) to obtain 2.62 g of a crude product of xanthene-9-carboxylic acid chloride. NMR δppm (CDCl3): 5.35 (s, 1
H), 7.06-7.30 (m, 8H) b) Example 1 using 2.62 g of the acid chloride synthesized above
-b) to obtain a crude product of 1-formyl-4-(xanthene-9-carbonyl)piperazine at 3.91%
I got g. NMR δppm (CDCl3): 2.94-3.8
0 (m, 8H), 5.45 (s, 1H), 6.97-7
.. 25 (m, 8H), 7.84 (s, 1H) c) Using 3.91 g of the formylpiperazine compound synthesized above, a reaction was performed according to Example 1-c) to obtain N-(xanthene-9-carbonyl). 2.38 g of piperazine was obtained. m. p. 146.1-147.5°C NMR δppm (CDCl3): 2.20-2.8
0 (m, 4H), 3.00-3.50 (m, 4H), 5
.. 35 (s, 1H), 6.90-7.2 (m, 8H) d
) 1.03 g of the piperazine compound synthesized above was reacted according to Example 1-d), and the title compound was converted to 0.0.
876g was obtained. NMR δppm (CDCl3): 1.97 (br.
s, 1H), 2.17 (br.s, 1H), 2.47~
2.63 (m, 4H), 3.28-3.33 (m, 2H
), 3.69-3.73 (m, 2H), 4.07-4.
17 (m, 3H), 5.46 (s, 1H), 6.8-7
.. 7 (m, 8H), 8.52 (d, 1H), 8.90 (
dd, 1H) IR νcm-1 (KBr): 3188, 2933,
1630, 1579, 1457, 1260, 795, 7
20
【0025】実施例3
5−〔3−{4−(α,α−ビス(4−フロロフェニル
)アセチル)ピペラジン}−1−イル}−2−ヒドロキ
シプロポキシ〕キノリン
a)α,α−ビス(4−フロロフェニル)酢酸440m
gを用いて実施例1−a)に従って反応し、α,α−ビ
ス(4−フロロフェニル)アセチルクロリドの粗生成物
を0.46g得た。ついで実施例1−b)に従って反応
し、4−(α,α−ビス(4−フロロフェニル)アセチ
ル−1−ホルミルピペラジンの粗生成物を0.63g得
た。
NMR δppm(CDCl3):2.8〜3.7(
m,8H)、5.23(s,1H)、6.80〜7.2
6(m,8H)、7.95(s,1H)
b)上記によって合成されたホルミルピペラジン体の0
.63gを用いて実施例1−c)に従って反応し、α,
α−(4−フロロフェニル)アセチルピペラジンを26
5mg得た。
m.p.116.5〜117.5℃
NMR δppm(CDCl3):2.5〜3.0(
m,1H)、3.36〜3.8(m,4H)、5.75
(s,1H)、6.8〜7.4(m,8H)
c)上記によって合成されたピペラジン体203mgを
用いて実施例1−d)に従って反応し、表記化合物を2
74mg得た。
NMR δppm(CDCl3):2.26(m,1
H)、2.44〜2.51(m,2H)、2.57〜2
.7(m,3H)、3.34(br.s,1H)、3.
45〜3.5(m,2H)、3.7〜3.75(m,2
H)、4.11〜4.25(m,3H)、5.17(s
,1H)、6.86〜7.72(m,12H)、8.5
4(m,1H)、8.90(m,1H)IR νcm
−1(KBr):3215、2924、2812、16
42、1507、1460、1158、1221、80
3Example 3 5-[3-{4-(α,α-bis(4-fluorophenyl)acetyl)piperazin}-1-yl}-2-hydroxypropoxy]quinoline a) α,α-bis( 4-fluorophenyl)acetic acid 440m
Using g, the reaction was carried out according to Example 1-a) to obtain 0.46 g of a crude product of α,α-bis(4-fluorophenyl)acetyl chloride. The reaction was then carried out according to Example 1-b) to obtain 0.63 g of a crude product of 4-(α,α-bis(4-fluorophenyl)acetyl-1-formylpiperazine. NMR δppm (CDCl3): 2. 8-3.7(
m, 8H), 5.23 (s, 1H), 6.80-7.2
6 (m, 8H), 7.95 (s, 1H) b) 0 of the formylpiperazine compound synthesized above
.. 63 g of α,
α-(4-fluorophenyl)acetylpiperazine 26
I got 5 mg. m. p. 116.5-117.5°C NMR δppm (CDCl3): 2.5-3.0 (
m, 1H), 3.36-3.8 (m, 4H), 5.75
(s, 1H), 6.8-7.4 (m, 8H) c) Using 203 mg of the piperazine compound synthesized above, the reaction was carried out according to Example 1-d) to convert the title compound into 2
74 mg was obtained. NMR δppm (CDCl3): 2.26 (m, 1
H), 2.44-2.51 (m, 2H), 2.57-2
.. 7 (m, 3H), 3.34 (br.s, 1H), 3.
45-3.5 (m, 2H), 3.7-3.75 (m, 2H)
H), 4.11-4.25 (m, 3H), 5.17 (s
, 1H), 6.86-7.72 (m, 12H), 8.5
4 (m, 1H), 8.90 (m, 1H) IR νcm
-1 (KBr): 3215, 2924, 2812, 16
42, 1507, 1460, 1158, 1221, 80
3
【0026】実施例4
5−〔3−{4−(フルオレン−9−カルボニル)ピペ
ラジン−1−イル}−2−ヒドロキシプロポキシ〕キノ
リン
フルオレン−9−カルボン酸2.1gを用いて実施例1
に従って単離することなく反応し、表記化合物を90m
g得た。
NMR δppm(CDCl3):2.2〜3.3(
m,10H)、4.0〜4.5(m,3H)、5.10
(s,1H)、6.88(d,1H)、7.4〜7.6
(m,9H)、7.82(d,2H)、8.62(d,
1H)、8.83(t,1H)
IR νcm−1(KBr):3424、1636、
1445、1266、1096、803、741Example 4 Example 1 using 2.1 g of 5-[3-{4-(fluorene-9-carbonyl)piperazin-1-yl}-2-hydroxypropoxy]quinolinefluorene-9-carboxylic acid
The title compound was reacted without isolation according to
I got g. NMR δppm (CDCl3): 2.2-3.3 (
m, 10H), 4.0 to 4.5 (m, 3H), 5.10
(s, 1H), 6.88 (d, 1H), 7.4-7.6
(m, 9H), 7.82 (d, 2H), 8.62 (d,
1H), 8.83 (t, 1H) IR νcm-1 (KBr): 3424, 1636,
1445, 1266, 1096, 803, 741
【00
27】実施例5
5−〔3−{4−(10,11−ジヒドロ−5H−ジベ
ンゾ〔b,f〕アゼピン−5−カルボニル)ピペラジン
−1−イル}−2−ヒドロキシプロポキシ〕キノリンa
)無水ピペラジン20gを100mlのジオキサンに加
え、ついでイミノジベンジル−5−カルボニルクロリド
10gを加えた。4時間加熱還流したのち溶媒を減圧留
去し、残渣に水を加えたのちCHCl3 で抽出した。
乾燥濃縮後、シリカゲルカラム(CHCl3 :MeO
H=10:1)で精製し、N−(10,11−ジヒドロ
−5H−ジベンゾ〔b,f〕アゼピン−5−カルボニル
)ピペラジン10.5gを得た。
NMR δppm(CDCl3):1.79(s,1
H)、2.70(t,4H)、3.15(s,4H)、
3.31(q,4H)、7.07〜7.26(m,6H
)、7.45(dd,2H)
IR νcm−1(KBr):3400、2840、
1640、1480、1440、1400、1280、
1250
b)上記によって合成されたピペラジン体2.15gを
用いて実施例1−d)に従って反応し、表記化合物を2
.9g得た。
NMR δppm(CDCl3):2.32〜2.3
9(m,2H)、2.53〜2.61(m,4H)、3
.15(s,4H)、3.32〜3.44(m,4H)
、4.11〜4.22(m,3H)、6.86(d,1
H)、7.09〜7.21(m,6H)、7.34〜7
.71(m,5H)、8.55(dd,1H)、8.9
1(dd,1H)
IR νcm−1(KBr):3400、1640、
1595、1490、1415、1380、128000
27 Example 5 5-[3-{4-(10,11-dihydro-5H-dibenzo[b,f]azepine-5-carbonyl)piperazin-1-yl}-2-hydroxypropoxy]quinoline a
) 20 g of anhydrous piperazine were added to 100 ml of dioxane followed by 10 g of iminodibenzyl-5-carbonyl chloride. After heating under reflux for 4 hours, the solvent was distilled off under reduced pressure, water was added to the residue, and the mixture was extracted with CHCl3. After drying and concentration, silica gel column (CHCl3:MeO
H=10:1) to obtain 10.5 g of N-(10,11-dihydro-5H-dibenzo[b,f]azepine-5-carbonyl)piperazine. NMR δppm (CDCl3): 1.79 (s, 1
H), 2.70 (t, 4H), 3.15 (s, 4H),
3.31 (q, 4H), 7.07-7.26 (m, 6H
), 7.45 (dd, 2H) IR νcm-1 (KBr): 3400, 2840,
1640, 1480, 1440, 1400, 1280,
1250 b) Using 2.15 g of the piperazine compound synthesized above, the reaction was carried out according to Example 1-d) to convert the title compound into 2.
.. I got 9g. NMR δppm (CDCl3): 2.32-2.3
9 (m, 2H), 2.53-2.61 (m, 4H), 3
.. 15 (s, 4H), 3.32-3.44 (m, 4H)
, 4.11-4.22 (m, 3H), 6.86 (d, 1
H), 7.09-7.21 (m, 6H), 7.34-7
.. 71 (m, 5H), 8.55 (dd, 1H), 8.9
1 (dd, 1H) IR νcm-1 (KBr): 3400, 1640,
1595, 1490, 1415, 1380, 1280
【
0028】試験例1 薬剤耐性癌細胞内への抗癌剤取
り込み増強効果
ヒト卵巣癌細胞A2780のアドリアマイシン耐性株2
780AD(A.M.Roganら,Science,
224巻,994−996頁、1984年)を5%牛胎
児血清を含むRPMI−1640培養液中に1×106
個/ml懸濁し、直径16cm、24穴のマルチウエ
ル培養プレートに1穴あたり1mlの癌細胞懸濁液を播
種し、5%CO2、37℃で培養した。24時間後に培
養液を20nM 3H−ビンクリスチン(1×104
dpm/pmol)、5%牛胎児血清、10mMヘペス
緩衝液を含むRPMI−1640培養液0.5ml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5μl加え(反応液中濃度は1.0
または10.0μg/ml)、5%CO2 、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0.5mlの0.2NNaOH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4m
l加え、液体シンチレーションカウンターで細胞内に取
り込まれた 3H−ビンクリスチンの量を測定した。[
Test Example 1 Effect of enhancing anticancer drug uptake into drug-resistant cancer cells Adriamycin-resistant strain 2 of human ovarian cancer cell A2780
780AD (A.M. Logan et al., Science,
224, pp. 994-996, 1984) at 1 x 106 in RPMI-1640 medium containing 5% fetal bovine serum.
1 ml of cancer cell suspension per well was seeded in a 24-well multi-well culture plate with a diameter of 16 cm, and cultured at 37° C. and 5% CO 2 . After 24 hours, the culture solution was treated with 20 nM 3H-vincristine (1 x 104
dpm/pmol), 5% fetal bovine serum, and 10 mM Hepes buffer. After dissolving in DMSO, 5 μl of the test compound diluted with physiological phosphate buffer was added (the concentration in the reaction solution was 1.0
After continuing to incubate for 2 hours at 37° C. or 10.0 μg/ml) and 5% CO 2 , the cells were washed with cold physiological phosphate buffer. 0.5 ml of 0.2 N NaOH was added to this, transferred to a vial, and bathed at 56° C. for 30 to 60 minutes to lyse the cells. Acid Aquasol 2 4m
1 was added, and the amount of 3H-vincristine taken into the cells was measured using a liquid scintillation counter.
【0029】効果は薬物無処理の対照群に取り込まれた
ビンクリスチンの量を100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
。結果を表1に示す。The effect was expressed as a percentage (%) of the amount of vincristine taken up by the drug-treated group, with the amount of vincristine taken up by the drug-untreated control group being taken as 100. The results are shown in Table 1.
【0030】[0030]
【表1】[Table 1]
Claims (1)
及びその塩。 【化1】 【化2】 ここでR1 はハロゲン原子、低級アルキル基、低級ア
ルコキシ基を表わす。) 【請求項2】 下記一般式(2)で表わされる請求項
1に記載の化合物。 【化3】 (式中R1は一般式(1)と同じ意味を表わす。)【請
求項3】 一般式(1)で表わされる化合物が5
−〔3−{4−(フルオレン−9−カルボニル)ピペラ
ジン−1−イル}−2−ヒドロキシプロポキシ〕キノリ
ンである請求項1に記載の化合物。 【請求項4】 一般式(1)で表わされる化合物
が5−〔3−{4−(キサンテン−9−カルボニル)ピ
ペラジン−1−イル}−2−ヒドロキシプロポキシ〕キ
ノリンである請求項1に記載の化合物。 【請求項5】 一般式(1)で表わされる化合物
が5−〔3−{4−(10,11−ジヒドロ−5H−ジ
ベンゾ〔b,f〕アゼピン−5−カルボニル)ピペラジ
ン−1−イル}−2−ヒドロキシプロポキシ〕キノリン
である請求項1に記載の化合物。 【請求項6】 請求項1に記載された一般式(1)で
表わされる化合物及びその塩を有効成分として成る制癌
剤効果増強剤。 【請求項7】 制癌剤が非代謝拮抗剤である請求
項6に記載の制癌剤効果増強剤。 【請求項8】 非代謝拮抗剤がビンクリスチン、
アドリアマイシンまたはエトポシドである請求項7に記
載の制癌剤効果増強剤。 【請求項9】 制癌剤効果増強剤が錠剤、顆粒剤
、散剤、懸濁剤、乳化剤、カプセル剤またはシロップ剤
である経口投与剤であるかまたは注射剤、座剤、輸液用
等張液である請求項6に記載の制癌剤効果増強剤。 【請求項10】 5−(2,3−エポキシプロポキシ
)キノリンと相当するアミン誘導体を熱的あるいは塩基
存在下反応させることにより一般式(1)の化合物を合
成する方法。[Scope of Claims] [Claim 1] A compound represented by general formula (1) and a salt thereof. [Formula 1] [Formula 2] Here, R1 represents a halogen atom, a lower alkyl group, or a lower alkoxy group. ) [Claim 2] The compound according to Claim 1, which is represented by the following general formula (2). [Claim 3] (In the formula, R1 has the same meaning as in the general formula (1).) [Claim 3] The compound represented by the general formula (1) is 5
The compound according to claim 1, which is -[3-{4-(fluorene-9-carbonyl)piperazin-1-yl}-2-hydroxypropoxy]quinoline. 4. The compound represented by the general formula (1) is 5-[3-{4-(xanthene-9-carbonyl)piperazin-1-yl}-2-hydroxypropoxy]quinoline. compound. 5. The compound represented by the general formula (1) is 5-[3-{4-(10,11-dihydro-5H-dibenzo[b,f]azepine-5-carbonyl)piperazin-1-yl} 2. The compound according to claim 1, which is -2-hydroxypropoxy]quinoline. 6. An anticancer drug effect enhancer comprising a compound represented by the general formula (1) according to claim 1 and a salt thereof as an active ingredient. 7. The anticancer drug effect enhancer according to claim 6, wherein the anticancer drug is a non-antimetabolite. [Claim 8] The non-antimetabolite is vincristine,
The anticancer drug effect enhancer according to claim 7, which is adriamycin or etoposide. 9. The anticancer drug effect enhancer is an oral preparation in the form of a tablet, granule, powder, suspension, emulsifier, capsule, or syrup, or an injection, suppository, or isotonic solution for infusion. The anticancer drug effect enhancer according to claim 6. 10. A method for synthesizing a compound of general formula (1) by reacting 5-(2,3-epoxypropoxy)quinoline and a corresponding amine derivative thermally or in the presence of a base.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2508291A JPH04356466A (en) | 1991-01-28 | 1991-01-28 | New quinoline derivative and carcinostatic agent effect enhancer containing the derivative as active ingredient |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2508291A JPH04356466A (en) | 1991-01-28 | 1991-01-28 | New quinoline derivative and carcinostatic agent effect enhancer containing the derivative as active ingredient |
Publications (1)
Publication Number | Publication Date |
---|---|
JPH04356466A true JPH04356466A (en) | 1992-12-10 |
Family
ID=12156008
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2508291A Pending JPH04356466A (en) | 1991-01-28 | 1991-01-28 | New quinoline derivative and carcinostatic agent effect enhancer containing the derivative as active ingredient |
Country Status (1)
Country | Link |
---|---|
JP (1) | JPH04356466A (en) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1996031111A1 (en) * | 1995-04-07 | 1996-10-10 | Schering Corporation | Tricyclic compounds useful in the treatment of cell proliferative disorders |
US6693099B2 (en) | 2000-10-17 | 2004-02-17 | The Procter & Gamble Company | Substituted piperazine compounds optionally containing a quinolyl moiety for treating multidrug resistance |
US11084807B2 (en) | 2016-08-18 | 2021-08-10 | Vidac Pharama Ltd. | Piperazine derivatives, pharmaceutical compositions and methods of use thereof |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH03101662A (en) * | 1988-10-06 | 1991-04-26 | Mitsui Toatsu Chem Inc | Novel heterocyclic compound and anticancer effect-enhancing agent containing the same compound as active ingredient |
-
1991
- 1991-01-28 JP JP2508291A patent/JPH04356466A/en active Pending
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH03101662A (en) * | 1988-10-06 | 1991-04-26 | Mitsui Toatsu Chem Inc | Novel heterocyclic compound and anticancer effect-enhancing agent containing the same compound as active ingredient |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1996031111A1 (en) * | 1995-04-07 | 1996-10-10 | Schering Corporation | Tricyclic compounds useful in the treatment of cell proliferative disorders |
US6693099B2 (en) | 2000-10-17 | 2004-02-17 | The Procter & Gamble Company | Substituted piperazine compounds optionally containing a quinolyl moiety for treating multidrug resistance |
US11084807B2 (en) | 2016-08-18 | 2021-08-10 | Vidac Pharama Ltd. | Piperazine derivatives, pharmaceutical compositions and methods of use thereof |
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