JPS6323173B2 - - Google Patents
Info
- Publication number
- JPS6323173B2 JPS6323173B2 JP62065350A JP6535087A JPS6323173B2 JP S6323173 B2 JPS6323173 B2 JP S6323173B2 JP 62065350 A JP62065350 A JP 62065350A JP 6535087 A JP6535087 A JP 6535087A JP S6323173 B2 JPS6323173 B2 JP S6323173B2
- Authority
- JP
- Japan
- Prior art keywords
- alkyl group
- lower alkyl
- compound
- anticancer agent
- agent according
- 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.)
- Expired
Links
- 150000001875 compounds Chemical class 0.000 claims description 56
- 239000002246 antineoplastic agent Substances 0.000 claims description 20
- 125000000217 alkyl group Chemical group 0.000 claims description 18
- 239000004480 active ingredient Substances 0.000 claims description 11
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 8
- -1 piperidylmethyl group Chemical group 0.000 claims description 8
- 150000003839 salts Chemical class 0.000 claims description 7
- 125000005277 alkyl imino group Chemical group 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 5
- 125000003282 alkyl amino group Chemical group 0.000 claims description 4
- 239000002552 dosage form Substances 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- 150000002790 naphthalenes Chemical class 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- 125000001997 phenyl group Chemical class [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- 125000004076 pyridyl group Chemical group 0.000 claims description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 27
- 210000004027 cell Anatomy 0.000 description 24
- 238000012360 testing method Methods 0.000 description 19
- 238000004519 manufacturing process Methods 0.000 description 16
- 239000000203 mixture Substances 0.000 description 16
- 206010028980 Neoplasm Diseases 0.000 description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- 230000001093 anti-cancer Effects 0.000 description 12
- 239000002775 capsule Substances 0.000 description 11
- 239000000126 substance Substances 0.000 description 11
- 201000011510 cancer Diseases 0.000 description 10
- 238000009472 formulation Methods 0.000 description 10
- 239000000243 solution Substances 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- 230000000694 effects Effects 0.000 description 8
- 239000008187 granular material Substances 0.000 description 7
- KUCOHFSKRZZVRO-UHFFFAOYSA-N terephthalaldehyde Chemical compound O=CC1=CC=C(C=O)C=C1 KUCOHFSKRZZVRO-UHFFFAOYSA-N 0.000 description 7
- 102000004142 Trypsin Human genes 0.000 description 6
- 108090000631 Trypsin Proteins 0.000 description 6
- 241000700605 Viruses Species 0.000 description 6
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- 235000002639 sodium chloride Nutrition 0.000 description 6
- 239000012588 trypsin Substances 0.000 description 6
- 239000011248 coating agent Substances 0.000 description 5
- 238000000576 coating method Methods 0.000 description 5
- 238000010253 intravenous injection Methods 0.000 description 5
- 231100000590 oncogenic Toxicity 0.000 description 5
- 230000002246 oncogenic effect Effects 0.000 description 5
- 208000024891 symptom Diseases 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- MEKOFIRRDATTAG-UHFFFAOYSA-N 2,2,5,8-tetramethyl-3,4-dihydrochromen-6-ol Chemical compound C1CC(C)(C)OC2=C1C(C)=C(O)C=C2C MEKOFIRRDATTAG-UHFFFAOYSA-N 0.000 description 3
- 229920000623 Cellulose acetate phthalate Polymers 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 150000003934 aromatic aldehydes Chemical class 0.000 description 3
- 239000006285 cell suspension Substances 0.000 description 3
- 229920002678 cellulose Polymers 0.000 description 3
- 239000001913 cellulose Substances 0.000 description 3
- 229940081734 cellulose acetate phthalate Drugs 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000012153 distilled water Substances 0.000 description 3
- 239000012530 fluid Substances 0.000 description 3
- 239000001963 growth medium Substances 0.000 description 3
- 229940088597 hormone Drugs 0.000 description 3
- 239000005556 hormone Substances 0.000 description 3
- 239000004615 ingredient Substances 0.000 description 3
- 231100000053 low toxicity Toxicity 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 239000003921 oil Substances 0.000 description 3
- 235000019198 oils Nutrition 0.000 description 3
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- HXKKHQJGJAFBHI-UHFFFAOYSA-N 1-aminopropan-2-ol Chemical compound CC(O)CN HXKKHQJGJAFBHI-UHFFFAOYSA-N 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- 238000011735 C3H mouse Methods 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- 229920000858 Cyclodextrin Polymers 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- 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 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- 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 2
- 241001465754 Metazoa Species 0.000 description 2
- BAPJBEWLBFYGME-UHFFFAOYSA-N Methyl acrylate Chemical compound COC(=O)C=C BAPJBEWLBFYGME-UHFFFAOYSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 239000002671 adjuvant Substances 0.000 description 2
- 229940041181 antineoplastic drug Drugs 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 230000004663 cell proliferation Effects 0.000 description 2
- 239000012829 chemotherapy agent Substances 0.000 description 2
- 239000007931 coated granule Substances 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 239000002662 enteric coated tablet Substances 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
- 235000013355 food flavoring agent Nutrition 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 230000009036 growth inhibition Effects 0.000 description 2
- 239000001307 helium Substances 0.000 description 2
- 229910052734 helium Inorganic materials 0.000 description 2
- SWQJXJOGLNCZEY-UHFFFAOYSA-N helium atom Chemical compound [He] SWQJXJOGLNCZEY-UHFFFAOYSA-N 0.000 description 2
- 239000011261 inert gas Substances 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 230000000968 intestinal effect Effects 0.000 description 2
- 229940102253 isopropanolamine Drugs 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 239000000314 lubricant 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
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 2
- 230000010534 mechanism of action Effects 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 239000002504 physiological saline solution Substances 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 239000008159 sesame oil Substances 0.000 description 2
- 235000011803 sesame oil Nutrition 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 238000010254 subcutaneous injection Methods 0.000 description 2
- 235000000346 sugar Nutrition 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 239000004094 surface-active agent Substances 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 description 2
- 238000010998 test method Methods 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- NOOLISFMXDJSKH-UTLUCORTSA-N (+)-Neomenthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@@H]1O NOOLISFMXDJSKH-UTLUCORTSA-N 0.000 description 1
- NNJPGOLRFBJNIW-HNNXBMFYSA-N (-)-demecolcine Chemical compound C1=C(OC)C(=O)C=C2[C@@H](NC)CCC3=CC(OC)=C(OC)C(OC)=C3C2=C1 NNJPGOLRFBJNIW-HNNXBMFYSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- JLPULHDHAOZNQI-ZTIMHPMXSA-N 1-hexadecanoyl-2-(9Z,12Z-octadecadienoyl)-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C/C\C=C/CCCCC JLPULHDHAOZNQI-ZTIMHPMXSA-N 0.000 description 1
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 1
- JCBPETKZIGVZRE-UHFFFAOYSA-N 2-aminobutan-1-ol Chemical compound CCC(N)CO JCBPETKZIGVZRE-UHFFFAOYSA-N 0.000 description 1
- BKMMTJMQCTUHRP-UHFFFAOYSA-N 2-aminopropan-1-ol Chemical compound CC(N)CO BKMMTJMQCTUHRP-UHFFFAOYSA-N 0.000 description 1
- 229940105325 3-dimethylaminopropylamine Drugs 0.000 description 1
- 229920002126 Acrylic acid copolymer Polymers 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
- 108010006654 Bleomycin Proteins 0.000 description 1
- 235000003351 Brassica cretica Nutrition 0.000 description 1
- 235000003343 Brassica rupestris Nutrition 0.000 description 1
- 241000219193 Brassicaceae Species 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytarabine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-CCXZUQQUSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- NOOLISFMXDJSKH-UHFFFAOYSA-N DL-menthol Natural products CC(C)C1CCC(C)CC1O NOOLISFMXDJSKH-UHFFFAOYSA-N 0.000 description 1
- NNJPGOLRFBJNIW-UHFFFAOYSA-N Demecolcine Natural products C1=C(OC)C(=O)C=C2C(NC)CCC3=CC(OC)=C(OC)C(OC)=C3C2=C1 NNJPGOLRFBJNIW-UHFFFAOYSA-N 0.000 description 1
- 239000001116 FEMA 4028 Substances 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 1
- 229930182816 L-glutamine Natural products 0.000 description 1
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 description 1
- CERQOIWHTDAKMF-UHFFFAOYSA-M Methacrylate Chemical compound CC(=C)C([O-])=O CERQOIWHTDAKMF-UHFFFAOYSA-M 0.000 description 1
- VVQNEPGJFQJSBK-UHFFFAOYSA-N Methyl methacrylate Chemical compound COC(=O)C(C)=C VVQNEPGJFQJSBK-UHFFFAOYSA-N 0.000 description 1
- 229930192392 Mitomycin Natural products 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 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 1
- 235000019502 Orange oil Nutrition 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 235000019485 Safflower oil Nutrition 0.000 description 1
- 239000002262 Schiff base Substances 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 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
- YKTSYUJCYHOUJP-UHFFFAOYSA-N [O--].[Al+3].[Al+3].[O-][Si]([O-])([O-])[O-] Chemical compound [O--].[Al+3].[Al+3].[O-][Si]([O-])([O-])[O-] YKTSYUJCYHOUJP-UHFFFAOYSA-N 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- WNLRTRBMVRJNCN-UHFFFAOYSA-N adipic acid Chemical class OC(=O)CCCCC(O)=O WNLRTRBMVRJNCN-UHFFFAOYSA-N 0.000 description 1
- 230000001919 adrenal effect Effects 0.000 description 1
- 229940009456 adriamycin Drugs 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- CEGOLXSVJUTHNZ-UHFFFAOYSA-K aluminium tristearate Chemical compound [Al+3].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CEGOLXSVJUTHNZ-UHFFFAOYSA-K 0.000 description 1
- 229940063655 aluminum stearate Drugs 0.000 description 1
- WMGSQTMJHBYJMQ-UHFFFAOYSA-N aluminum;magnesium;silicate Chemical compound [Mg+2].[Al+3].[O-][Si]([O-])([O-])[O-] WMGSQTMJHBYJMQ-UHFFFAOYSA-N 0.000 description 1
- CBTVGIZVANVGBH-UHFFFAOYSA-N aminomethyl propanol Chemical compound CC(C)(N)CO CBTVGIZVANVGBH-UHFFFAOYSA-N 0.000 description 1
- 229950000242 ancitabine Drugs 0.000 description 1
- KZOWNALBTMILAP-JBMRGDGGSA-N ancitabine hydrochloride Chemical compound Cl.N=C1C=CN2[C@@H]3O[C@H](CO)[C@@H](O)[C@@H]3OC2=N1 KZOWNALBTMILAP-JBMRGDGGSA-N 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000000340 anti-metabolite Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 229940100197 antimetabolite Drugs 0.000 description 1
- 239000002256 antimetabolite Substances 0.000 description 1
- 229940045719 antineoplastic alkylating agent nitrosoureas Drugs 0.000 description 1
- 229940045713 antineoplastic alkylating drug ethylene imines Drugs 0.000 description 1
- 150000001555 benzenes Chemical class 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- WHGYBXFWUBPSRW-FOUAGVGXSA-N beta-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO WHGYBXFWUBPSRW-FOUAGVGXSA-N 0.000 description 1
- 235000011175 beta-cyclodextrine Nutrition 0.000 description 1
- 229960004853 betadex Drugs 0.000 description 1
- 229960001561 bleomycin Drugs 0.000 description 1
- OYVAGSVQBOHSSS-UAPAGMARSA-O bleomycin A2 Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCC[S+](C)C)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1N=CNC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C OYVAGSVQBOHSSS-UAPAGMARSA-O 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229960005069 calcium Drugs 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 235000010216 calcium carbonate Nutrition 0.000 description 1
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 description 1
- MKJXYGKVIBWPFZ-UHFFFAOYSA-L calcium lactate Chemical compound [Ca+2].CC(O)C([O-])=O.CC(O)C([O-])=O MKJXYGKVIBWPFZ-UHFFFAOYSA-L 0.000 description 1
- 239000001527 calcium lactate Substances 0.000 description 1
- 235000011086 calcium lactate Nutrition 0.000 description 1
- 229960002401 calcium lactate Drugs 0.000 description 1
- 244000309466 calf Species 0.000 description 1
- 150000001719 carbohydrate derivatives Chemical class 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 229960004106 citric acid Drugs 0.000 description 1
- 150000001860 citric acid derivatives Chemical class 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 229940043241 conventional cytotoxic antineoplastic drug Drugs 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
- 239000006059 cover glass Substances 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 229940127089 cytotoxic agent Drugs 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- KXGVEGMKQFWNSR-LLQZFEROSA-N deoxycholic acid Chemical compound C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 KXGVEGMKQFWNSR-LLQZFEROSA-N 0.000 description 1
- 229960003964 deoxycholic acid Drugs 0.000 description 1
- 235000019700 dicalcium phosphate Nutrition 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- IUNMPGNGSSIWFP-UHFFFAOYSA-N dimethylaminopropylamine Chemical compound CN(C)CCCN IUNMPGNGSSIWFP-UHFFFAOYSA-N 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000235 effect on cancer Effects 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 1
- 239000010642 eucalyptus oil Substances 0.000 description 1
- 229940044949 eucalyptus oil Drugs 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 150000002191 fatty alcohols Chemical class 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-L fumarate(2-) Chemical class [O-]C(=O)\C=C\C([O-])=O VZCYOOQTPOCHFL-OWOJBTEDSA-L 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 210000004051 gastric juice Anatomy 0.000 description 1
- 229960001031 glucose Drugs 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 239000007902 hard capsule Substances 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- 229940031704 hydroxypropyl methylcellulose phthalate Drugs 0.000 description 1
- 229960001438 immunostimulant agent Drugs 0.000 description 1
- 239000003022 immunostimulating agent Substances 0.000 description 1
- 230000003308 immunostimulating effect Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 210000003292 kidney cell Anatomy 0.000 description 1
- 231100001231 less toxic Toxicity 0.000 description 1
- 229940069445 licorice extract Drugs 0.000 description 1
- 239000006194 liquid suspension Substances 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000002075 main ingredient Substances 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 229940049920 malate Drugs 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
- 235000011090 malic acid Nutrition 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 229940099690 malic acid Drugs 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229940041616 menthol Drugs 0.000 description 1
- 229920003145 methacrylic acid copolymer Polymers 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 239000003094 microcapsule Substances 0.000 description 1
- 229960004857 mitomycin Drugs 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 235000010460 mustard Nutrition 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 239000010502 orange oil Substances 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 125000005498 phthalate group Chemical class 0.000 description 1
- XNGIFLGASWRNHJ-UHFFFAOYSA-L phthalate(2-) Chemical compound [O-]C(=O)C1=CC=CC=C1C([O-])=O XNGIFLGASWRNHJ-UHFFFAOYSA-L 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- OXNIZHLAWKMVMX-UHFFFAOYSA-N picric acid Chemical class OC1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-N 0.000 description 1
- DBMHTLOVZSDLFD-UHFFFAOYSA-N piperidin-1-ylmethanamine Chemical compound NCN1CCCCC1 DBMHTLOVZSDLFD-UHFFFAOYSA-N 0.000 description 1
- 239000004014 plasticizer Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 108010001062 polysaccharide-K Proteins 0.000 description 1
- 150000004032 porphyrins Chemical class 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 229940081974 saccharin Drugs 0.000 description 1
- 235000019204 saccharin Nutrition 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- 239000003813 safflower oil Substances 0.000 description 1
- 235000005713 safflower oil Nutrition 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000008347 soybean phospholipid Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 150000003890 succinate salts Chemical class 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 125000001273 sulfonato group Chemical class [O-]S(*)(=O)=O 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 150000003892 tartrate salts Chemical class 0.000 description 1
- WFWLQNSHRPWKFK-ZCFIWIBFSA-N tegafur Chemical compound O=C1NC(=O)C(F)=CN1[C@@H]1OCCC1 WFWLQNSHRPWKFK-ZCFIWIBFSA-N 0.000 description 1
- 229960001674 tegafur Drugs 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 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
- 238000012546 transfer Methods 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
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Description
ãç£æ¥äžã®å©çšåéã
æ¬çºæã¯å¶çå€ã«é¢ããã
ãçºæã®èæ¯ã
åŸæ¥ãçååŠçæ³å€ãšããŠãã¢ã«ãã«åå€ïŒã
ã€ãããŒã³ãã¹ã¿ãŒãé¡ããšãã¬ã³ã€ãã³é¡ãã¹
ã«ããªã³é
žãšã¹ãã«é¡ãããããœãŠã¬ã¢é¡ïŒã代
è¬æ®æç©è³ªïŒã¡ããã¬ãã»ãŒããããã©ããŒã«ã
ã·ãã·ã³ã¢ã©ãããµã€ããã·ã¯ãã·ããžã³çïŒã
æ€ç©æ§æçå€ïŒã³ã«ã»ããããã³ãã©ã¹ãã³ãã
ããã€ãªã³çïŒãæçç©è³ªïŒãã¬ãªãã€ã·ã³ãã¢
ããªã¢ãã€ã·ã³ããã€ããã€ã·ã³çïŒããã«ã¢ã³
é¡ãïŒå¯è
ã¹ããã€ããç·æ§ãã«ã¢ã³ã女æ§ãã«
ã¢ã³ïŒãå
ç«è³ŠæŽ»å€ïŒã¯ã¬ã¹ãã³ããã·ãããŒã«
çïŒåã³ãã«ãã€ãªã³é¯å¡©ïŒããŒãã€ãªã³ã
COPPïŒçãçšããããŠãããäžè¬ã«å¶çç©è³ªã®
äœçšã¯ç现èã ãã§ãªãæ£åžžçŽ°èã«ãäœçšããã
ãã«æ¯æ§ã匷ããé倧ãªå¯äœçšãåããã®ã§ãæ
æçã«å¯ŸããååŠçæ³å€ã®åŠã倧éã®è¬å€ã䜿çš
ããããšã«ãã€ãŠååãªå¹æããããããšã¯å°é£
ãªçŸç¶ã«ããã
ãçºæã®ç®çã
ãããã€ãŠæ¬çºæã®ç®çã¯ããã®ãããªå¯äœçš
ã®ãªããæ°èŠãªå¶çå€ãæäŸããããšã§ããã
ãçºæã®æ§æã
æ¬çºæã¯äžèšã®äžè¬åŒïŒïŒã§è¡šããããåå
ç©ãŸãã¯ãã®è¬ççã«èš±å®¹ãããé
žéå å¡©ãæå¹
æåãšããŠå«æããå¶çå€ã§ããã
Râ²âÏâCHïŒïŒ®â ïŒïŒ
åŒäžÏã¯ãã³ãŒã³æ žåã¯ããã¿ã¬ã³æ žãè¡šã
ãã
ã¯äœçŽã¢ã«ãã«åºãããããã·äœçŽã¢ã«ãã«
åºãäœçŽã¢ã«ãã«ã¢ããäœçŽã¢ã«ãã«åºãããªãž
ã«åºããããªãžã«ã¡ãã«åºãããããã·ããšãã«
åºãŸãã¯ãã³ãžãªãã³ã¢ããäœçŽã¢ã«ãã«åº
ãè¡šããã
Râ²ã¯æ°ŽçŽ ãäœçŽã¢ã«ãã«ã€ããäœçŽã¢ã«ãã«
åºãäœçŽã¢ã«ãã«ã¢ãäœçŽã¢ã«ãã«ã€ããäœçŽã¢
ã«ãã«åºãŸãã¯ããããã·äœçŽã¢ã«ãã«ã€ããäœ
çŽã¢ã«ãã«åºãè¡šããã
äœããÏãããã¿ã¬ã³æ žãè¡šããå Žåã«ã¯ã
ã¯äœçŽã¢ã«ãã«åºãŸãã¯ããããã·äœçŽã¢ã«
ãã«åºãRâ²ã¯æ°ŽçŽ ãè¡šããã
äžèšåŒïŒïŒã®ååç©ã®è¬ççã«èš±å®¹ãããé
ž
éå å¡©ãšã¯å¡©åºå¡©ãç¡«é
žå¡©ããã¯ãªã³é
žå¡©ãã¯ãš
ã³é
žå¡©ãé
ç³é
žå¡©ãããã«é
žå¡©ããã¿ã«é
žå¡©ãã³
ãã¯é
žå¡©ãã¢ãžãã³é
žå¡©ãã·ãŠãŠé
žå¡©ãããã³é
ž
å¡©ããã¬ã€ã³é
žå¡©ããªã³ãŽé
žå¡©çã§ãããããã
ã®å¡©ã¯åŒïŒïŒã®ååç©ããåžžæ³ã«ãã容æã«åŸ
ãããšãåºæ¥ãã
åŒïŒïŒã«å«ãŸããå
¬ç¥ååç©ãããããå¶ç
æ§ãæããããšã«ã€ããŠã¯æªã ç¥ãããŠããªãã
åŒïŒïŒã®ååç©ã¯äœãããã³ãºã¢ã«ãããåã¯
ãã¬ãã¿ã«ã¢ã«ãããã®ã·ããå¡©åºèªå°äœãšããŠ
èããããšãåºæ¥ããã®ã§ããã
æ¬çºæè
ã¯ãå
ã«ãã³ãºã¢ã«ããããæå¹æå
ãšããæ°èŠäžã€æçšãªå¶çå€ãéçºãïŒç¹éæ52
â108027å·å
¬å ±åç
§ïŒããã®æå¹æåã®äœçšãç
现èãçŽæ¥æ»æãããã®ã§ã¯ãªããåŸæ¥èããã
ãŠæ¥ãååŠçæ³å€ãšã¯å¥ç°ã®äœçšæ©äœã§æ²»çå¹æ
ãçãããã®ãšèããããç¹ç°çãªæçäœçšã§ã
ãããšãæ°ãã«èŠåºããããæŽã«å¶ç掻æ§ç©è³ªã®
æ¢çŽ¢ã«ã€ããŠéæç 究ã®çµæãåŒïŒïŒã®è³éŠæ
ã¢ã«ãããèªå°äœãããããé¡èãªå¶ç掻æ§ãæ
ããäºãèŠåºãããããã®ç©è³ªãçæ²»çã«é¡èãª
å¹æãçºæ®ãåŸãããšã®æ°ããªç¥èŠãåŸãŠããã«
æ¬çºæã®å¶çå€ãå®æããã
åŸæ¥ã®çååŠçæ³å€ã®å€ããSV40çºçãŠã€ã«
ã¹ã«ããçå现èããããšãŒã«ãªããè
«çãªã©ã®
移æ€çã«å¯ŸããŠæåæ§ãé«ããããããçäœçŽ°è
æ¯æ§åã®ç©è³ªã§ããã®ã«å¯Ÿããæ¬çºæã®å¶çå€ã®
æå¹æåã¯ãSV40çºçãŠã€ã«ã¹ã«ãã€ãŠçåã
ã现èã«äœçšããŠé«ãæåæ§ã瀺ãç¹ã«ãããŠã
åŸæ¥ã®çååŠçæ³å€ã®äœçšæ©äœãšã¯ç°ãªãç¹ç°ç
ãªå¶çäœçšã«åºã¥ããã®ãšèããããå¶çå€ãšã
ãŠããããç¹è²ãæãããã®ã§ããã
æ¬çºæã«çšããå¶ç掻æ§ãæããåŒïŒïŒã®è³
éŠæã¢ã«ãããèªå°äœãäŸç€ºããã°ç¬¬ïŒè¡šã®ãšã
ãã§ããã
[Industrial Field of Application] The present invention relates to an anticancer agent. [Background of the Invention] Conventionally, cancer chemotherapy agents include alkylating agents (nitrozene mustards, ethyleneimines, sulfonate esters, nitrosoureas), antimetabolites (methotrexate, ftorafur,
cytosine arabinoside, cyclocytidine, etc.),
Botanical anticancer agents (colcemid, vinblastine, podophyrin, etc.), antibiotics (bleomycin, adriamycin, mitomycin, etc.), hormones (adrenal steroids, male hormones, female hormones), immunostimulants (krestin, picibanil, etc.), and porphyrin complex salts ( Mahfilin,
Anticancer substances (COPP), etc. are used, but in general, anticancer substances act not only on cancer cells but also on normal cells, so they are highly toxic and have serious side effects. At present, it is difficult to achieve sufficient effects through the use of drugs. [Object of the Invention] Therefore, an object of the present invention is to provide a novel anticancer agent that does not have such side effects. [Structure of the Invention] The present invention is an anticancer agent containing a compound represented by the following general formula () or a pharmacologically acceptable acid salt thereof as an active ingredient. R'-Ï-CH=N-R () In the formula, Ï represents a benzene nucleus or a naphthalene nucleus, and R is a lower alkyl group, a hydroxy lower alkyl group, a lower alkylamino lower alkyl group, a pyridyl group, a piperidylmethyl group, a hydroxy It represents a phenyl group or a benzylideneamino lower alkyl group, and R' represents hydrogen, a lower alkylimino lower alkyl group, a lower alkylamino lower alkylimino lower alkyl group or a hydroxy lower alkylimino lower alkyl group. However, when Ï represents a naphthalene nucleus, R represents a lower alkyl group or a hydroxy lower alkyl group, and R' represents hydrogen. Pharmaceutically acceptable acid addition salts of the compound of the above formula () are base salts, sulfates, picrates, citrates, tartrates, fumarates, phthalates, succinates, and adipates. , oxalate, malonate, maleate, malate, etc., and these salts can be easily obtained from the compound of formula () by conventional methods. The known compounds contained in formula () are also not yet known to have anticancer properties.
Any compound of formula () can be considered as a Schiff base derivative of benzaldehyde or terephthalaldehyde. The present inventor previously developed a new and useful anticancer agent containing benzaldehyde as an active ingredient (Japanese Patent Application Laid-open No.
(Refer to Publication No. 108027), the action of this active ingredient does not directly attack cancer cells, but is thought to produce therapeutic effects through a mechanism of action that is different from that of conventionally thought chemotherapeutic agents. Furthermore, as a result of intensive research into the search for anticancer active substances, it was discovered that the aromatic aldehyde derivatives of formula () each have remarkable anticancer activity. The anticancer agent of the present invention has now been completed based on new findings that the substance can exert a remarkable effect on cancer treatment. Most conventional cancer chemotherapeutic agents are so-called cytotoxic substances, which are more sensitive to transplanted cancers such as Ehrlichi tumors than to cancerous cells caused by the SV 40 oncogenic virus. The active ingredient exhibits high sensitivity by acting on cells that have become cancerous due to the SV 40 oncogenic virus.
It is thought to be based on a specific anticancer effect that is different from the mechanism of action of conventional cancer chemotherapeutic agents, and has excellent characteristics as an anticancer agent. Examples of the aromatic aldehyde derivatives of formula () having anticancer activity used in the present invention are shown in Table 1.
ãè¡šããtableã
ãè¡šã
äžèšååç©(1)ãïŒ18ïŒïŒä»¥äžãäžèšååç©ã¯å
åç©çªå·ããã€ãŠç€ºããïŒã«ã€ããŠã®åèæç®å
ã³ç©æ§å€ã第ïŒè¡šã«ç€ºãã[Table] References and physical property values for the above compounds (1) to (18) (hereinafter, the above compounds are indicated by compound numbers) are shown in Table 2.
ãè¡šããtableã
ãè¡šããtableã
ãè¡šã
補é äŸ ïŒ
ïŒååç©(1)ã®è£œæ³ïŒ
ãã³ãºã¢ã«ããããšçã¢ã«ã®ã¿ãŒã·ã€ãªããã«
ã¢ãã³ãç¡æ°Žãã³ãŒã³äžã§å
±æ²žããŠããæ°Žãé€å»
ããªããïŒæééæµåŸããã³ãŒã³ãæžå§äžã«çå»
ããèžçããããšã«ãã€ãŠååç©(1)ãåŸãããã
補é äŸ ïŒ
ïŒååç©(2)ã®è£œæ³ïŒ
ãã³ãºã¢ã«ããããšçã¢ã«ã®ãããªãžã«ã¡ãã«
ã¢ãã³ãç¡æ°Žãã³ãŒã³äžã§å
±æ²žããŠããæ°Žãé€å»
ããªããïŒæééæµåŸããã³ãŒã³ãæžå§äžã«çå»
ãã150ã153âïŒïŒmmHgã®èžçåºåãååç©(2)
ãšããŠåŸãã
補é äŸ ïŒ
ïŒååç©(6)ã®è£œæ³ïŒ
ãã¬ãã¿ã«ã¢ã«ããããšå€§éå°ã®70ïŒ
ãšãã«ã¢
ãã³æ°Žæº¶æ¶²ãïŒæ¥é宀枩ã«ãŠåå¿ãããåžžæ³åŠç
ããŠåçµæ¶ããããšã«ããååç©(6)ãåŸãããã
補é äŸ ïŒ
ïŒååç©(7)ã®è£œæ³ïŒ
ãã¬ãã¿ã«ã¢ã«ããããšå€§éå°ã®70ïŒ
ã¿ãŒã·ã€
ãªããã«ã¢ãã³æ°Žæº¶æ¶²ãïŒæ¥é宀枩ã«ãŠåå¿ãã
ãåŸãæªåå¿ç©ãæžå§äžæºå»ããŠååç©(7)ãåŸ
ãã
補é äŸ ïŒ
ïŒååç©(8)ã®è£œæ³ïŒ
ãã¬ãã¿ã«ã¢ã«ããããšïŒåã¢ã«ã®ïŒâãžã¡ã
ã«ã¢ããâãããã«ã¢ãã³ãç¡æ°Žãã³ãŒã³äžã§å
±
沞ããŠããæ°Žãé€å»ããªããïŒæééæµããæžå§
äžããã³ãŒã³åã³æªåå¿ç©ãçå»ããŠååç©(8)ã
åŸãã
補é äŸ ïŒ
ïŒååç©(9)åã³(10)ã®è£œæ³ïŒ
ãã¬ãã¿ã«ã¢ã«ããããšïŒåã¢ã«ã®ã€ãœããã
ããŒã«ã¢ãã³ãç¡æ°Žãã³ãŒã³äžã§å
±æ²žããŠããæ°Ž
ãé€å»ããªããïŒæééæµåŸãåžžæ³åŠçããã€ãœ
ãããã«ãšãŒãã«ãšãšã¿ããŒã«ïŒïŒïŒæ··å溶åªã§
åçµæ¶ããŠååç©(9)ãåŸããïŒâã¢ããâãžã¡ã
ã«ãšã¿ããŒã«ãçšããŠäžèšãç¹°è¿ãååç©(10)ãåŸ
ãã
補é äŸ ïŒ
ïŒååç©(11)åã³(12)ã®è£œæ³ïŒ
ãã¬ãã¿ã«ã¢ã«ããããšïŒåã¢ã«ã®ïŒâã¢ãã
âïŒâãã¿ããŒã«ãç¡æ°Žãã³ãŒã³äžã§å
±æ²žããŠã
ãæ°Žãé€å»ããªããïŒæééæµåŸãåžžæ³åŠçãã
ãšã¿ããŒã«ããåçµæ¶ããŠååç©(11)ãåŸãããšã¿
ããŒã«ã¢ãã³ãçšããŠäžèšãç¹°è¿ãååç©(12)ãåŸ
ãã
補é äŸ ïŒ
ïŒååç©(11)ã®è£œæ³ïŒ
ãã¬ãã¿ã«ã¢ã«ããããšïŒåã¢ã«ã®ïŒâã¢ãã
âïŒâãããããŒã«ãç¡æ°Žãã³ãŒã³äžã§å
±æ²žããŠ
ããæ°Žãé€å»ããªããïŒæééæµåŸãåžžæ³åŠç
ãããšã¿ããŒã«ããåçµæ¶ããŠååç©(11)ãåŸãã
æ¬çºæã®å¶çå€ã¯ãçµå£åã³éçµå£æäžã®ãã
ãã䜿çšå¯èœã§ãããçµå£æäžããå Žåã¯ãè»ã»
硬ã«ãã»ã«å€åã¯é å€ãé¡ç²å€ã现ç²å€ãæ£å€ãš
ããŠæäžãããéçµå£æäžããå Žåã¯ã泚å°å€ã
ç¹æ»Žå€åã³åºäœç¶åã¯æžæ¿ç²çš 液ç¶ãšããŠæç¶ç
ãªç²èåžåãç¶æã§ããããã«åè¬ã®ãããªå€å
ã§æäžããåŸãã
æ¬çºæã®å¶çå€çµæç©ã®æå¹æåã®å²åã¯ãå€
åã«ãã€ãŠå€æŽãåŸãããéåžžãçµå£åã¯ç²èåž
åã«æäžããããšããã»ãŒ0.3ã15.0ééïŒ
ãé©
åœã§ãããéçµå£æäžããããšãã¯ãã»ãŒ0.01ã
10ééïŒ
ãé©åœã§ããã
ãŸããæ¬çºæã®æå¹æåã補å€åããã«åœã€ãŠ
ã¯ãäžèšåŒïŒïŒã®è³éŠæã¢ã«ãããèªå°äœã¯åžž
æ³ã«åŸãã氎溶æ§æžæ¿æ¶²ãæ²¹æ§è£œå€ãªã©ã«ããŠç®
äžæãã¯éè泚å°çšè£œå€ãšããããšãã§ããä»ã
ã«ãã»ã«å€ãé å€ã现ç²å€çã®å€åã«è£œå€åããŠ
çµå£çšã«äŸããããšãã§ããã
æ¬çºæã®æå¹æåã®è£œå€åã«çšããããçé¢æŽ»
æ§å€ã賊圢å€ãæ»æ²¢å€ãäœå€åã³å»è¬çã«èš±å®¹ã
åŸãç®è圢æç©è³ªçãæããã°ã次ã®ãšããã§ã
ãã
æ¬çºæã®çµæç©ã®åŽ©å£ã溶åºãè¯å¥œãªãããã
ããã«ãçé¢æŽ»æ§å€ãäŸãã°ã¢ã«ã³ãŒã«ããšã¹ã
ã«é¡ãããªãšãã¬ã³ã°ãªã³ãŒã«èªå°äœããœã«ãã¿
ã³ã®èèªé
žãšã¹ãã«é¡ãç¡«é
žåèèªã¢ã«ã³ãŒã«é¡
çã®ïŒçš®åã¯ïŒçš®ä»¥äžãæ·»å ããããšãã§ããã
ãŸãã賊圢å€ãšããŠãäŸãã°èç³ãä¹³ç³ããã³
ãã³ãçµæ¶ã»ã«ããŒã¹ããã³ãããã軜質ç¡æ°Žçª
é
žãã¢ã«ãã³é
žãã°ãã·ãŠã ãã¡ã¿çªé
žã¢ã«ãé
ž
ãã°ãã·ãŠã ãåæçªé
žã¢ã«ãããŠã ãçé
žã«ã«
ã·ãŠã ãçé
žæ°ŽçŽ ãããªãŠã ããªã³é
žæ°ŽçŽ ã«ã«ã·
ãŠã ãã«ã«ããã·ã¡ãã«ã»ã«ããŒã¹ã«ã«ã·ãŠã ç
ã®ïŒçš®åã¯ïŒçš®ä»¥äžãçµåããŠæ·»å ããããšãã§
ããã
æ»æ²¢å€ãšããŠã¯ãäŸãã°ã¹ãã¢ãªã³é
žãã°ãã·
ãŠã ãã¿ã«ã¯ã硬åæ²¹çãïŒçš®åã¯ïŒçš®ä»¥äžæ·»å
ããããšãã§ãããŸãç¯å³å€åã³ç¯èå€ãšããŠã
é£å¡©ããµãã«ãªã³ãç³ããã³ãããããªã¬ã³ãž
æ²¹ãã«ã³ãŸãŠãšãã¹ãã¯ãšã³é
žããããŠç³ãã¡ã³
ããŒã«ããŠãŒã«ãªæ²¹ããªã³ãŽé
žçã®çå³å€ãéŠ
æãçè²æãä¿åæçãå«æãããŠãããã
æžæ¿å€ã湿最å€ã®åŠãäœå€ãšããŠã¯ãäŸãã°ã³
ããããæ²¹ããªãªãŒãæ²¹ããŽãæ²¹ãèœè±çæ²¹ãä¹³
é
žã«ã«ã·ãŠã ãããããæ²¹ã倧è±ãªã³è質çãå«
æãããããšãã§ããã
ãŸããç®è圢æç©è³ªãšããŠã¯ãã»ã«ããŒã¹ã»ç³
é¡çã®çæ°Žåç©èªå°äœãšããŠé
¢é
žãã¿ã«é
žã»ã«ã
ãŒã¹ïŒCAPïŒããŸãã¢ã¯ãªã«é
žç³»å
±éåäœãäºå¡©
åºé
žã¢ããšã¹ãã«é¡çã®ããªããã«èªå°äœãšããŠ
ã¢ã¯ãªã«é
žã¡ãã«ã»ã¡ã¿ã¢ã¯ãªã«é
žå
±éåäœãã¡
ã¿ã¢ã¯ãªã«é
žã¡ãã«ã»ã¡ã¿ã¢ã¯ãªã«é
žå
±éåçã
æããããã
ãŸããäžèšç®è圢æç©è³ªãã³ãŒãã€ã³ã°ããã«
éããé垞䜿çšãããã³ãŒãã€ã³ã°å©å€ãäŸãã°
å¯å¡å€ã®ä»ãã³ãŒãã€ã³ã°æäœæã®è¬å€çžäºã®ä»
çé²æ¢ã®ããã®å皮添å å€ãæ·»å ããããšã«ãã€
ãŠç®è圢æå€ã®æ§è³ªãæ¹è¯ããããã³ãŒãã€ã³ã°
æäœããã容æãªããããããšãã§ããã
ãŸããäŸãã°ãã³ã¬ã€ã³é
žãã·ã¯ãããã¹ããª
ã³ïŒCyclodextrinïŒã®å
æ¥èœãå©çšããè¬ççã«
蚱容ãããå
æ¥ååç©ãšããããšãé©åœã§ããã
ãŸããã€ã¯ãã«ãã»ã«ã«ãã補å€åãæçšã§ã
ãã
ãŸããäžèšå
æ¥ååç©ãé·æéã®ä¿æã«èãã
å®å®æ§åã³èé
žæ§ãéäžããŠè¬å¹ãå®å
šã«æç¶ã
ããããã«ãæŽã«å»è¬çã«èš±å®¹ãåŸãç®èãæœã
ãŠè£œå€åããã°ãããããå®å®æ§ãæããå¶çå€
çµæç©ãšããããšãã§ããã
ãŸããæäžéã¯ãææã®æ²»çå¹æåã³æ²»çæé
ã«ãã€ãŠå·Šå³ããããã倧人ã§ã¯éåžžãïŒæ¥åœã
äžèšååç©ãšããŠ0.5ã5000mgãå°äººã§ã¯éåžžã
0.5ã3000mgã§ããã
次ã«ãäžèšååç©ã®å¶ç掻æ§ã確èªããå¶çæ§
è©Šéšæ³ã«ã€ããŠè¿°ã¹ãã
C3HããŠã¹ã®è
现èãSV40çºçãŠã€ã«ã¹ã§ç
åããã现èW2Kã»11ãäŸè©ŠçŽ°èãšããããã
次ã®æ¹æ³ã«ãã€ãŠå¹é€ããã
(1) å¢æ®å¹é€æ¶²ã®èª¿è£œ
ã€ãŒã°ã«MEMå¹å°9.4ïœãèžçæ°Ž900mlã«æº¶
ããã120âã15åéå å§æ»
èããå·åŽåŸãä»
çè¡æž
100mlåã³å¥é115âã
15åéå å§æžèãã10ïŒ
çé
žæ°ŽçŽ ãããªãŠã
液ãïŒãïŒmlå ããŠPH7.1ã7.2ã«è£æ£ãããå¹
å°äœ¿çšçŽåã«ããªãã¢ã»ãã€ã«ã¿ãŒã§æ¿Ÿéãã
âã°ã«ã¿ãã³ïŒ2.92ïœïŒ100mlïŒæº¶æ¶²10mlã
å ããã
ãªããäŸè©ŠçŽ°èã®ä¿åã«ã¯ãæŽã«æçµæ¿åºŠ10
ïŒ
ã®ãžã¡ãã«ã¹ã«ãããµã€ããå ããã
(2) 移æ®çŽ°èã®èª¿è£œ
ãžãŒãã»ããªãŒã¶ãŒïŒâ80âïŒã§ä¿åããã
äŸè©ŠçŽ°èã宀枩ã§æº¶è§£ããã670ÃïŒåéé å¿
åé¢ããŠäžæž
ãæšãŠãæ²æ®¿ãã现èãå¢æ®å¹å°
50mlã«æžæ¿ããåŸã«ã«ãŒã»ãã©ã¹ã³ã«ç§»ãã37
âã§å¹é€ãããšã现èã¯ãã©ã¹ã³åºé¢ã«éçã
ãªããå¢æ®ãå§ããïŒãïŒæ¥ã§ååã«å¢æ®ã
ããå¹é€æ¶²ããã«ã³ããã次ãã§0.2ïŒ
ããªã
ã·ã³æº¶æ¶²ãã€ãŒã°ã«MEMå¹å°ïŒæ¥æ¬è£œè¬(æ ª)
補ïŒ4.7ïœãéæ¹0.6ïœåã³ããªãã·ã³ïŒïœãèž
çæ°Ž500mlã«æº¶ãããããªãã¢ã»ãã€ã«ã¿ãŒã§
æ¿Ÿéãã溶液ã10mlãå ããŠå®€æž©ã§ïŒãïŒåé
ããªãã·ã³åŠçããåŸãããªãã·ã³æº¶æ¶²ããã«
ã³ããããæŽã«æ°é®®ãªå¢æ®å¹å°50mlãå ããé§
蟌ããããã§éçããŠãã现èãæŽãèœããŠçŽ°
èæµ®é液ãšãããäžéšã¯ã«ãŒã»ãã©ã¹ã³ãçšã
ãŠç¶ä»£å¹é€ããã
(3) 现èå¹é€ãšè¢«éšååç©ã®æäž
åèšçŽ°èæµ®é液1.8mlããã€ã¹ããŒã¶ã«ã»ã·
ã€ãŒã¬ïŒçŽåŸ35mmïŒã«å泚ããçé
žã¬ã¹ã€ã³ã
ãŠããŒã¿ãŒïŒïŒïŒ
CO2ã95ïŒ
空æ°ïŒäžã§37âã
24æéå¹é€ããã
ãã®æç¹ã§è¢«éšååç©ã®æº¶æ¶²0.2mlãæäžã
ãŠå¹é€ãç¶ç¶ããã
现èå¢æ®ã®ç¶æ
ã¯ãåç«é¡åŸ®é¡ãçšããŠé£æ¥
芳å¯ããæäžåŸã48æéã«çŽ°èã®çåæ°ãæ°ã
ãããªãã被éšååç©ã¯ãèžçæ°Žåã¯ãšã¿ããŒ
ã«ïŒæçµæ¿åºŠïŒïŒ
ïŒã«æº¶è§£ãããåŸãããªã
ã¢ã»ãã€ã«ã¿ãŒã§æ¿Ÿéããã
(4) 现èæ°ã®æ°ãæ¹
被éšååç©æäžåŸã48æéã®ã·ã€ãŒã¬ããã«
ã³ãããŠäžæž
ïŒå¹é€æ¶²ïŒãæšãŠãåèš0.2ïŒ
ã
ãªãã·ã³æº¶æ¶²1.0mlã§ã·ã€ãŒã¬ã®åºã«éçãã
现èãåŠçãããšå现èã«ãªããããããã«ã³
ãããŠããªãã·ã³æº¶æ¶²ãé€å»ãã10ããªã¢ã«ã®
çé
žç·©è¡æ¶²ïŒPH7.0ïŒãå«ãççé£å¡©æ°Žã§çŽ°è
æµ®é液ãäœãããã®äžéšã®ïŒãªããïŒæ»Žãè¡ç
èšç®æ¿ã«ãšããã«ããŒã°ã©ã¹ããã¶ããŠé¡åŸ®é¡
äžã§çŽ°èæ°ãæ°ããã
äŸè©ŠçŽ°èå¢æ®ã®æå¶çã¯ã次åŒã«ããæ±ã
ãã
æå¶çïŒïŒ
ïŒïŒ
ïŒè¢«éšååç©ç¡æäžã·ã€ãŒã¬äžã®çŽ°èæ°ïŒâïŒè¢«éšå
åç©æäžã·ã€ãŒã¬äžã®çŽ°èæ°ïŒïŒïŒè¢«éšååç©ç¡æäžã·
ã€ãŒã¬äžã®çŽ°èæ°ïŒÃ100
次ã«ãæ¬çºæã®æå¹æåã®ååç©ã®æ¯æ§ã«ã€ã
ãŠã¯ããããã®ååç©ãäœååæ§é ã®ããã«éã
ã«çäœå€ã«ææ³ãããã®ã§å¯äœçšãçããªãã
ãšããŸãããŠã¹ã®ç®äžæ³šå°åã³çµå£æäžã«ããã
LD50å€ãããããä»ã®å¶çç©è³ªã«æ¯ãäœæ¯æ§ã§
ãããäžèšååç©ã®ããŠã¹ã®çµå£æäžã®å Žåã®
LD50ïŒmgïŒKgïŒã¯ããããã第ïŒè¡šã®ãšããã§ã
ãã
以äžã«ãæ¬çºæã補å€äŸåã³è©ŠéšäŸã«ãã€ãŠå
·
äœçã«èª¬æããã
補å€äŸ ïŒ
ïŒæ³šå°ã»ç¹æ»Žå€ïŒ
äžèšååç©(12)500mgãå«æããããã«ç²æ«ã¶ã©
ãç³ïŒïœãå ããŠãã€ã¢ã«ã«ç¡èçã«åé
ããå¯
å°ããäžãçªçŽ ãããªãŠã çã®äžæŽ»æ§ã¬ã¹ãå°å
¥
ããŠå·ææã«ä¿åããã䜿çšåã«ã0.85ïŒ
ççç
é£å¡©æ°Ž500mlãæ·»å ããŠéèå
泚å°å€ãšããïŒæ¥ã
10ã500mlãçç¶ã«å¿ããŠéèå
泚å°åã¯ç¹æ»Žã§
æäžããã
補å€äŸ ïŒ
ïŒæ³šå°ã»ç¹æ»Žå€ïŒ
äžèšååç©(11)50mgãçšããä»ã¯ã補å€äŸïŒãšå
æ§ã®æ¹æ³ã«ãã軜ççšéèå
泚å°å€ãšããïŒæ¥ã
10ã500mlãçç¶ã«å¿ããŠéèå
泚å°åã¯ç¹æ»Žã§
æäžããã
補å€äŸ ïŒ
ïŒæ³šå°å€ãã«ãã»ã«å€ïŒ
äžèšååç©(6)30mgã粟補ãŽãæ²¹ïŒïœåã³ã¹ãã¢
ãªã³é
žã¢ã«ãããŠã ã²ã«100mgã«æº¶è§£ãå¯å°ãã
äžãçªçŽ ãããªãŠã çã®äžæŽ»æ§ã¬ã¹ãå°å
¥ããŠå·
ææã«ä¿åããç®äžæ³šå°çšè£œå€ãšãããçç¶ã«å¿
ããŠïŒæ¥ã«ïŒåãïŒã10mlãç®äžæ³šå°ã§æäžã
ãã
ãŸããåèšè£œå€ã0.5mlã¥ã€ã«ãã»ã«ã«å泚ã
ãŠçµå£çšã«ãã»ã«å€ãšããïŒæ¥ãïŒã10ã«ãã»ã«
ãçç¶ã«å¿ããŠçµå£æäžããã
補å€äŸ ïŒ
ïŒè
žæº¶æ§é å€ïŒ
βâã·ã¯ãããã¹ããªã³ïŒæ¥æ°Žé£ååå·¥(æ ª)補ïŒ
ã®é£œå氎溶液3000mlã«äžèšååç©(1)15ïœãå
¥ããŠ
æ··åããïŒæéæªæãããšå
æ¥ç©ãæ²æ®¿ããã®
ã§ããã®æ²æ®¿ç©ãæžå§ä¹Ÿç¥ãããšã100ïœã®äžèš
ååç©(1)ã®å
æ¥ååç©ãåŸãããã
以äžã®æåçµæã§è
žæº¶æ§é å€å€§äººçš(ã€)åã³å°äºº
çš(ã)åã
1000åã補é ããã[Table] Production Example 1 (Production method of compound (1)) Tertiary butylamine in an equimolar amount as benzaldehyde was refluxed for 3 hours while removing azeotropic water in anhydrous benzene, and then the benzene was distilled off under reduced pressure. , Compound (1) is obtained by distillation. Production Example 2 (Production method for compound (2)) Piperidylmethylamine in an equimolar amount as benzaldehyde is refluxed for 3 hours while removing azeotropic water in anhydrous benzene, and then the benzene is distilled off under reduced pressure. Distillation section of 153â/2mmHg for compound (2)
get as. Production Example 3 (Production method of compound (6)) Compound (6) is obtained by reacting terephthalaldehyde and a large excess of 70% ethylamine aqueous solution at room temperature for 3 days, followed by recrystallization by conventional treatment. Production Example 4 (Production method for compound (7)) After reacting terephthalaldehyde and a large excess of 70% tertiary butylamine aqueous solution at room temperature for 3 days, unreacted substances were distilled off under reduced pressure to obtain compound (7). . Production Example 5 (Production of Compound (8)) Terephthalaldehyde and 2 times the mole of 3-dimethylamino-propylamine were refluxed for 3 hours while removing azeotropic water in anhydrous benzene, and then the benzene and Unreacted substances are distilled off to obtain compound (8). Production Example 6 (Production of Compounds (9) and (10)) Terephthalaldehyde and 2 times the mole of isopropanolamine were refluxed for 3 hours while removing azeotropic water in anhydrous benzene, and then treated in a conventional manner to produce isopropanolamine. Recrystallize from a 1:1 mixed solvent of ether and ethanol to obtain compound (9). The above procedure is repeated using 2-amino-dimethylethanol to obtain compound (10). Production Example 7 (Production method for compounds (11) and (12)) Terephthalaldehyde and 2 times the mole of 2-amino-1-butanol were refluxed in anhydrous benzene for 3 hours while removing azeotropic water, and then refluxed for 3 hours. legal processing,
Recrystallization from ethanol yields compound (11). The above procedure is repeated using ethanolamine to obtain compound (12). Production Example 8 (Production of Compound (11)) Terephthalaldehyde and 2 times the mole of 2-amino-1-propanol were refluxed for 3 hours while removing azeotropic water in anhydrous benzene, and then treated in a conventional manner. Recrystallization from ethanol yields compound (11). The anticancer agent of the present invention can be administered either orally or parenterally.
Administered as hard capsules, tablets, granules, fine granules, or powders; when administered parenterally, injections,
It can be administered in a dosage form such as a suppository so as to maintain sustained mucosal absorption in the form of a drop, a solid or a viscous liquid suspension. The proportion of the active ingredient in the anticancer drug composition of the present invention may vary depending on the dosage form, but usually approximately 0.3 to 15.0% by weight is appropriate when administered orally or by mucosal absorption, and when administered parenterally, When the value is approximately 0.01~
10% by weight is suitable. Furthermore, when formulating the active ingredient of the present invention, the aromatic aldehyde derivative of the above formula () can be made into a water-soluble suspension, oil-based preparation, etc., into a subcutaneous or intravenous injection preparation. In addition to being able to
It can be formulated into dosage forms such as capsules, tablets, and fine granules for oral use. The surfactants, excipients, lubricants, adjuvants, pharmaceutically acceptable film-forming substances, etc. used in formulating the active ingredient of the present invention are as follows. In order to improve disintegration and elution of the composition of the present invention, one or more surfactants such as alcohols, esters, polyethylene glycol derivatives, sorbitan fatty acid esters, sulfated fatty alcohols, etc. are added. Can be added. In addition, excipients such as sucrose, lactose, starch, crystalline cellulose, mannite, light silicic anhydride, magnesium aluminate, magnesium aluminate metasilicate, synthetic aluminum silicate, calcium carbonate, sodium hydrogen carbonate, calcium hydrogen phosphate, carboxylic Methylcellulose calcium and the like can be added alone or in combination of two or more. As a lubricant, for example, one or more types of magnesium stearate, talc, hydrogenated oil, etc. can be added, and as a flavoring agent and a flavoring agent,
Sweeteners such as salt, saccharin, sugar, mannitrite, orange oil, licorice extract, citric acid, glucose, menthol, eucalyptus oil, and malic acid, fragrances, colorants, preservatives, and the like may be included. Adjuvants such as suspending agents and wetting agents may include, for example, corona oil, olive oil, sesame oil, peanut oil, calcium lactate, safflower oil, soybean phospholipid, and the like. Film-forming substances include cellulose acetate phthalate (CAP) as a carbohydrate derivative such as cellulose and sugars, methyl acrylate and methacrylate as polyvinyl derivatives such as acrylic acid copolymers and dibasic acid monoesters. Examples include copolymers, methyl methacrylate/methacrylic acid copolymers, and the like. In addition, when coating the above-mentioned film-forming substance, in addition to commonly used coating aids such as plasticizers, various additives to prevent chemicals from adhering to each other during coating operations can be added to the film-forming agent. properties and make coating operations easier. In addition, for example, it is appropriate to use a pharmacologically acceptable clathrate compound that utilizes the clathration ability of choleic acid or cyclodextrin.
Formulation using microcapsules is also useful. In addition, in order to give the above-mentioned clathrate compound stability and acid resistance that can withstand long-term retention and to fully maintain its medicinal efficacy, it is possible to formulate a formulation with a pharmaceutically acceptable coating. A stable anticancer drug composition can be obtained. The dosage depends on the desired therapeutic effect and duration of treatment, but for adults it is usually 0.5 to 5000 mg of the above compound per day, and for children it is usually 0.5 to 5000 mg per day.
It is 0.5-3000mg. Next, the anticancer activity test method for confirming the anticancer activity of the above compound will be described. The test cells were W2K-11 cells obtained by turning C3H mouse kidney cells into cancer with the SV 40 oncogenic virus, and were cultured by the following method. (1) Preparation of growth culture solution Dissolve 9.4 g of Eagle MEM medium in 900 ml of distilled water, autoclave at 120°C for 15 minutes, cool, add 100 ml of calf serum and 10% autoclaved separately at 115°C for 15 minutes. Add 3-5 ml of sodium hydrogen carbonate solution to correct the pH to 7.1-7.2. Immediately before using the medium, add 10 ml of L-glutamine (2.92 g/100 ml) solution filtered through a Millipore filter. In addition, to preserve the test cells, the final concentration is 10.
% dimethyl sulfoxide. (2) Preparation of transplanted cells Test cells stored in a Jeep freezer (-80â) were lysed at room temperature, centrifuged at 670Ã for 5 minutes, the supernatant was discarded, and the precipitated cells were added to the growth medium.
After suspending in 50 ml, transfer to a roux flask and
When cultured at .degree. C., the cells begin to proliferate while adhering to the bottom of the flask, and fully proliferate in 3 to 4 days. Decant the culture solution and add 0.2% trypsin solution [Eagle MEM medium (Nippon Pharmaceutical Co., Ltd.)
Dissolve 4.7 g of the product, 0.6 g of sodium bicarbonate, and 1 g of trypsin in 500 ml of distilled water and filter it with a Millipore filter. Add 10 ml of the solution, treat with trypsin for 2 to 3 minutes at room temperature, and then decant the trypsin solution. Furthermore, add 50 ml of fresh growth medium and wash off adhering cells using a Komagome pipette to obtain a cell suspension. A portion is subcultured using Roux flasks. (3) Cell culture and administration of test compound Dispense 1.8 ml of the above cell suspension into a disposable chamber (diameter 35 mm) and incubate at 37°C in a carbon dioxide incubator (5% CO 2 , 95% air).
Incubate for 24 hours. At this point, 0.2 ml of the test compound solution is administered to continue the culture. The state of cell proliferation is observed every day using an inverted microscope, and the number of surviving cells is counted 48 hours after administration. The test compound is dissolved in distilled water or ethanol (final concentration 2%) and then filtered with a Millipore filter. (4) How to count the number of cells After administering the test compound, decant the shell for 48 hours, discard the supernatant (culture medium), and treat the cells attached to the bottom of the shell with 1.0 ml of the above 0.2% trypsin solution, resulting in single cells. Become. Decant this to remove the trypsin solution, make a cell suspension with physiological saline containing 10 mmol of phosphate buffer (PH7.0), place 1 to 2 drops of this on a hemocytometer, and put it on a cover glass. Count the number of cells under a microscope. The inhibition rate of test cell proliferation was determined by the following formula. Inhibition rate (%) = (Number of cells in a shear plate without administration of the test compound) - (Number of cells in a shear plate administered with a test compound) / (Number of cells in a shear plate without administration of a test compound) x 100 Next, the active ingredient of the present invention Concerning the toxicity of these compounds, all of them are rapidly excreted outside the body due to their low-molecular structure and do not cause any side effects.
Both LD 50 values are low toxicity compared to other anticancer substances, and the above compounds are less toxic when administered orally to mice.
LD 50 (mg/Kg) is shown in Table 3. The present invention will be specifically explained below using formulation examples and test examples. Formulation Example 1 (Injection/Drop) Add 5 g of powdered glucose to contain 500 mg of the above compound (12), dispense aseptically into vials, seal them, and fill with inert gas such as nitrogen or helium. Store in a cool, dark place. Before use, add 500 ml of 0.85% physiological saline to make an intravenous injection, and administer for one day.
Administer 10 to 500 ml by intravenous injection or drip depending on symptoms. Formulation Example 2 (Injection/Drop) An intravenous injection for mild symptoms was prepared in the same manner as Formulation Example 1, except that 50 mg of the above compound (11) was used, and administered for one day.
Administer 10 to 500 ml by intravenous injection or drip depending on symptoms. Formulation Example 3 (Injection, Capsule) 30 mg of the above compound (6) was dissolved in 1 g of purified sesame oil and 100 mg of aluminum stearate gel, sealed, sealed with an inert gas such as nitrogen or helium, and stored in a cool, dark place. Preparation for subcutaneous injection. Administer 1 to 10 ml subcutaneously once a day depending on the symptoms. In addition, the above preparation is dispensed into capsules in 0.5 ml portions to prepare oral capsules, and 1 to 10 capsules are orally administered per day depending on the symptoms. Formulation example 4 (enteric-coated tablet) β-cyclodextrin (manufactured by Nissui Foods Kako Co., Ltd.)
When 15 g of the above compound (1) is added to 3000 ml of a saturated aqueous solution and mixed and stirred for 5 hours, the clathrate precipitates. When this precipitate is dried under reduced pressure, 100 g of the clathrate compound of the above compound (1) is obtained. It will be done. Enteric-coated tablets (1) for adults and 1000 for children (2) were manufactured with the following ingredient composition.
äž»å€ïŒäžèšååç©(1)ã®å
æ¥ååç©ïŒ 100ïŒïœïŒ
ä¹³ ç³ 737
ããããã·ãããã«ã»ã«ããŒã¹ ïŒ
ãBã
é
¢é
žãã¿ã«é
žã»ã«ããŒã¹ 80ïŒïœïŒ
ããããã·ãããã«ã¡ãã«ã»ã«ããŒã¹ãã¿ã¬ãŒ
ã 80
ããã®æåãåã
ãšããããæ··åããåŸãåžž
æ³ã«åŸã€ãŠç²ç¶ã«æ圢ããããããã也ç¥ããŠç¯©
å¥ãããã³ãããŒãã·ãŒã«å
è£
ãªã©ã«é©ããé¡ç²
å€ã補é ããã次ã«ããã®é¡ç²ãæµ®éæµåãããª
ãã溶解ããããã®åºæã被èŠããè
žæº¶æ§ã®é¡
ç²å€ãšããããã®é¡ç²å€ã¯ãæ¥å±ã®åŽ©å£è©Šéšåšã
çšããŠåŽ©å£è©Šéšãè¡ã€ããšãããPH1.2ã®äººå·¥è
液ã«ïŒæéæ¯çªããŠã厩å£ããªããPH7.5ã®äººå·¥
è
žæ¶²ã§ã¯ïŒåã§åŽ©å£ããã
補å€äŸ ïŒ
ïŒè
žæº¶æ§ã«ãã»ã«å€ïŒ
以äžã®æåã§è
žæº¶æ§ã«ãã»ã«å€1000åã補é ã
ãã
Main ingredient (clathrate compound of compound (1) above) 100 (g) Lactose 737 Hydroxypropyl cellulose 3 [B] Cellulose acetate phthalate 80 (g) Hydroxypropyl methylcellulose phthalate 80 Take each component of [A] and mix well. After that, it was formed into granules according to a conventional method, thoroughly dried and sieved to produce granules suitable for bottles, heat-seal packaging, etc. Next, the granules are coated with the dissolved base material [B] while floating and flowing to form enteric-coated granules. When this granule was subjected to a disintegration test using a Japanese Pharmacopoeia disintegration tester, it did not disintegrate even when shaken in artificial gastric juice of pH 1.2 for one hour. In artificial intestinal fluid with a pH of 7.5, it disintegrated in 5 minutes. Formulation Example 6 (Enteric-coated capsules) 1000 enteric-coated capsules were manufactured using the following ingredients.
ãè¡šã
ã»ã«ããŒã¹ãã¿ã¬ãŒã
äžèšã®æåã§è£œå€äŸïŒã«èšèŒããåæ§ã®æ¹æ³ã§
ã«ãã»ã«çšã«é©ããè
žæº¶æ§ã®é¡ç²å€ã補é ããã
ã®çµæç©ãã«ãã»ã«ã«å
å¡«ããŠè
žæº¶æ§ã«ãã»ã«ãš
ããã
ãã®ã«ãã»ã«ã¯ãæ¥å±ã®åŽ©å£è©ŠéšåšãçšããŠåŽ©
å£è©Šéšãè¡ã€ããšãããPH1.2ã®äººå·¥è液ã«ïŒæ
éæ¯çªããŠã厩å£ãŸãã¯æº¶åºãèªãããPH7.5ã®
人工è
žæ¶²ã«ïŒåã§åŽ©å£ãŸãã¯å
šéã溶åºããã
è©ŠéšäŸ
äžèšååç©(1)ãïŒ14ïŒãçšããåèšè©Šéšæ³ã«ã
ãSV40çºçãŠã€ã«ã¹ã«ãã€ãŠçåããC3HããŠ
ã¹ã®ç现èW2Kã»11ã®å¢æ®æå¶çïŒïŒ
ïŒãç®åº
ãããšã第ïŒè¡šã«ç€ºãçµæãåŸãããã[Table] Cellulose phthalate Enteric-coated granules suitable for capsules were produced using the above ingredients in the same manner as described in Formulation Example 5, and the composition was filled into capsules to obtain enteric-coated capsules. When this capsule was subjected to a disintegration test using a Japanese Pharmacopoeia disintegration tester, no disintegration or dissolution was observed even after shaking in artificial gastric fluid at pH 1.2 for 1 hour, and no disintegration or dissolution was observed in artificial intestinal fluid at pH 7.5 in 5 minutes. Collapsed or the entire amount eluted. Test Example Using the above-mentioned compounds (1) to (14), the growth inhibition rate (%) of cancer cells W2K-11 of C3H mice that had become cancerous due to the SV 40 oncogenic virus was calculated according to the test method as shown in Table 3. The results shown are obtained.
è©ŠéšäŸã®çµæããæãããªããã«ãäžèšè¢«éšå
åç©ã¯ãããããå¶ç掻æ§ãæããããšãç«èšŒã
ããã
ãªããäžèšè¢«éšååç©äžãååç©(1)ã®æŽ»æ§å€ã
ä»ã®ååç©ã«æ¯ããŠäœãããããã¯åŸæ¥ã®çååŠ
çæ³å€ã®å€ããåç©ã®ç§»æ€çã«æ¯ããSV40çºç
ãŠã€ã«ã¹ã«ããçå现èã«æŽ»æ§ã極ããŠäœãã®ã«
察ããŠäžèšååç©ãããã«äœçšããŠæå¶å¹æã瀺
ããäžã€ããããã®ååç©ã極ããŠäœæ¯æ§ã§ãã
ããšã¯æ¥µããŠç¹åŸŽçã§ããããšã«æ³šç®ãã¹ãã§ã
ãã
ãŸããååç©(7)ã«é¢ããŠã¯äžèšã®è©Šéšæ¡ä»¶äžã§
ã¯10ÎŒïœïŒmlã§æé«ã®æº¶è§£åºŠã瀺ããçµæã§ãã
ããæŽã«æ¿åºŠãé«ããã°åœç¶ã«äžèšå¢æ®æå¶çã®
åäžãæåŸ
ããããã®ã§ããã
å³ã¡ãåŸæ¥ã®çŽ°èæ¯æ§åã®å¶çå€ã®å€ãã¯åç©
ã®å®éšè
«çãå³ã¡ç§»æ€çã«å¯ŸããŠé¡èãªæŽ»æ§ã瀺
ãã®ã«æ¯ãèšåºçã«ã¯å€ãã®åé¡ç¹ãæ®ããŠã
ããæå¹äŸã¯æ¥µããŠå°ãã®ãå®ç¶ã§ãã€ãŠããã
ã¯ç§»æ€çãšåçºçãšã®éã®æ ¹æ¬çãªå·®ç°ã«åºã¥ã
ãã®ãšèãããã人çºçãªåçºçãšãããã
SV40ãŠã€ã«ã¹èªçºçã«æŽ»æ§ãæããäžã€äœæ¯æ§
ã§ããäžèšååç©ã¯æ¥µããŠç¹åŸŽçãªå¶ç掻æ§ãæ
ãããã®ãšèªãããããã®ã§ããã
As is clear from the results of the test examples, it was demonstrated that the above test compound has excellent anticancer activity. Among the above test compounds, the activity value of Compound (1) is lower than that of the other compounds, but this is because most of the conventional cancer chemotherapy agents are used to treat cancers caused by the SV 40 oncogenic virus, compared to transplanted cancers in animals. It should be noted that the above-mentioned compounds act on these cells and exhibit an inhibitory effect, whereas the activity against these cells is extremely low, and all of the compounds are extremely characteristic in that they have extremely low toxicity. Furthermore, under the above test conditions, compound (7) showed the highest solubility at 10 ÎŒg/ml, but it is naturally expected that the above growth inhibition rate would improve if the concentration was further increased. In other words, although many of the conventional cytotoxic anticancer drugs show remarkable activity against experimental tumors in animals, that is, transplanted cancers, they still have many problems clinically, and there are very few effective examples. This is the actual situation, and this is thought to be based on the fundamental difference between transplanted cancer and primary cancer, and can be said to be an artificial primary cancer.
The above-mentioned compound, which is active against SV 40 virus-induced cancer and has low toxicity, is recognized to have very specific anticancer activity.
Claims (1)
ççã«èš±å®¹ãããé žéå å¡©ãæå¹æåãšããŠå«æ
ããå¶çå€ã Râ²âÏâCHïŒïŒ®â ïŒïŒ åŒäžÏã¯ãã³ãŒã³æ žåã¯ããã¿ã¬ã³æ žãè¡šã
ãã ã¯äœçŽã¢ã«ãã«åºãããããã·äœçŽã¢ã«ãã«
åºãäœçŽã¢ã«ãã«ã¢ããäœçŽã¢ã«ãã«åºãããªãž
ã«åºããããªãžã«ã¡ãã«åºãããããã·ããšãã«
åºãŸãã¯ãã³ãžãªãã³ã¢ããäœçŽã¢ã«ãã«åº ãè¡šããã Râ²ã¯æ°ŽçŽ ãäœçŽã¢ã«ãã«ã€ããäœçŽã¢ã«ãã«
åºãäœçŽã¢ã«ãã«ã¢ããäœçŽã¢ã«ãã«ã€ããäœçŽ
ã¢ã«ãã«åºãŸãã¯ããããã·äœçŽã¢ã«ãã«ã€ãã
äœçŽã¢ã«ãã«åºãè¡šããã äœããÏãããã¿ã¬ã³æ žãè¡šããå Žåã«ã¯ã
ã¯äœçŽã¢ã«ãã«åºãŸãã¯ããããã·äœçŽã¢ã«ãã«
åºãRâ²ã¯æ°ŽçŽ ãè¡šããã ïŒ åŒïŒïŒã®ååç©ãè¬ççã«èš±å®¹ãããå æ¥
ååç©ãšããŠçšããç¹èš±è«æ±ã®ç¯å²ç¬¬ïŒé èšèŒã®
å¶çå€ã ïŒ çµå£æäžå€ã§ããç¹èš±è«æ±ã®ç¯å²ç¬¬ïŒé èšèŒ
ã®å¶çå€ã ïŒ æå¹æåã0.3ã15.0ééïŒ ã®éå«æããç¹
èš±è«æ±ã®ç¯å²ç¬¬ïŒé èšèŒã®å¶çå€ã ïŒ éçµå£æäžå€ã§ããç¹èš±è«æ±ã®ç¯å²ç¬¬ïŒé èš
èŒã®å¶çå€ã ïŒ æå¹æåã0.01ã10ééïŒ ã®éå«æããç¹èš±
è«æ±ã®ç¯å²ç¬¬ïŒé èšèŒã®å¶çå€ã ïŒ è žæº¶æ§æäžåœ¢æ ããšãç¹èš±è«æ±ã®ç¯å²ç¬¬ïŒã
ïŒãïŒé ã®ãã¥ããã«èšèŒã®å¶çå€ã[Scope of Claims] An anticancer agent containing a compound represented by the following formula () or a pharmacologically acceptable acid salt thereof as an active ingredient. R'-Ï-CH=N-R () In the formula, Ï represents a benzene nucleus or a naphthalene nucleus, and R is a lower alkyl group, a hydroxy lower alkyl group, a lower alkylamino lower alkyl group, a pyridyl group, a piperidylmethyl group, a hydroxy It represents a phenyl group or a benzylideneamino lower alkyl group, and R' represents hydrogen, a lower alkylimino lower alkyl group, a lower alkylamino lower alkylimino lower alkyl group or a hydroxy lower alkylimino lower alkyl group. However, when Ï represents a naphthalene nucleus, R
represents a lower alkyl group or a hydroxy lower alkyl group, and R' represents hydrogen. 2. The anticancer agent according to claim 1, which uses the compound of formula () as a pharmacologically acceptable clathrate compound. 3. The anticancer agent according to claim 1, which is an orally administered agent. 4. The anticancer agent according to claim 3, which contains the active ingredient in an amount of 0.3 to 15.0% by weight. 5. The anticancer agent according to claim 1, which is a parenterally administered agent. 6. The anticancer agent according to claim 5, which contains the active ingredient in an amount of 0.01 to 10% by weight. 7. Claim 1, which takes an enteric-coated dosage form,
The anticancer agent according to any one of Items 3 and 5.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP62065350A JPS6310721A (en) | 1987-03-19 | 1987-03-19 | Carcinostatic agent |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP62065350A JPS6310721A (en) | 1987-03-19 | 1987-03-19 | Carcinostatic agent |
Publications (2)
Publication Number | Publication Date |
---|---|
JPS6310721A JPS6310721A (en) | 1988-01-18 |
JPS6323173B2 true JPS6323173B2 (en) | 1988-05-16 |
Family
ID=13284417
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP62065350A Granted JPS6310721A (en) | 1987-03-19 | 1987-03-19 | Carcinostatic agent |
Country Status (1)
Country | Link |
---|---|
JP (1) | JPS6310721A (en) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN106831485A (en) * | 2017-03-29 | 2017-06-13 | éœé²å·¥äžå€§åŠ | TwoïŒ4 methoxybenzylidenesïŒThe preparation and use of the diamines of butane 1,4 |
-
1987
- 1987-03-19 JP JP62065350A patent/JPS6310721A/en active Granted
Also Published As
Publication number | Publication date |
---|---|
JPS6310721A (en) | 1988-01-18 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
KR100311165B1 (en) | Pharmaceutical composition for treating depression containing pramifelsol | |
EA007613B1 (en) | A benzenesulfonate salt of (2s,4s)-2-cyano-4-fluoro-1-[(2-hydroxy-1,1-dimethyl)ethylamino]acethylpyrrolidine | |
WO2009140887A1 (en) | A scutellarin derivative, the preparing process, the pharmaceutical composition and the use thereof | |
JPS639493B2 (en) | ||
US8344017B2 (en) | Anti-hepatitis C virus agents and anti-HIV agents | |
JPS6352012B2 (en) | ||
JPS6310685B2 (en) | ||
JPS6334123B2 (en) | ||
JPS6334124B2 (en) | ||
JPS6323173B2 (en) | ||
JPS6261568B2 (en) | ||
JPS6352011B2 (en) | ||
JPH0158162B2 (en) | ||
JPS6334125B2 (en) | ||
BE1001704A3 (en) | Aqueous compositions containing acid derivative piperidinylcyclopentylheptenoique. | |
JPS63264409A (en) | Carcinostatic agent | |
JPS638085B2 (en) | ||
WO2005021481A1 (en) | N, nâ-dibenzyl ethylenediamine salt pf 2-(alpha-hidroxypentyl) benzoic acid and its preparing process and usage | |
JPS638086B2 (en) | ||
JPS6344725B2 (en) | ||
JPS6344126B2 (en) | ||
JPS639490B2 (en) | ||
JPS6334126B2 (en) | ||
JPS6334844B2 (en) | ||
JPS6344127B2 (en) |