JP2008545805A - 有糸分裂モータータンパク質eg5の調節剤の形態で使用されるテトラヒドロキノリン - Google Patents
有糸分裂モータータンパク質eg5の調節剤の形態で使用されるテトラヒドロキノリン Download PDFInfo
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- JP2008545805A JP2008545805A JP2008516172A JP2008516172A JP2008545805A JP 2008545805 A JP2008545805 A JP 2008545805A JP 2008516172 A JP2008516172 A JP 2008516172A JP 2008516172 A JP2008516172 A JP 2008516172A JP 2008545805 A JP2008545805 A JP 2008545805A
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- 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
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
- 229960001860 salicylate Drugs 0.000 description 1
- MOODSJOROWROTO-UHFFFAOYSA-N salicylsulfuric acid Chemical compound OC(=O)C1=CC=CC=C1OS(O)(=O)=O MOODSJOROWROTO-UHFFFAOYSA-N 0.000 description 1
- 229960005399 satraplatin Drugs 0.000 description 1
- 190014017285 satraplatin Chemical compound 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 125000003548 sec-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
- 238000007873 sieving Methods 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
- 210000003491 skin Anatomy 0.000 description 1
- 229950010372 sobuzoxane Drugs 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- RYYKJJJTJZKILX-UHFFFAOYSA-M sodium octadecanoate Chemical compound [Na+].CCCCCCCCCCCCCCCCCC([O-])=O RYYKJJJTJZKILX-UHFFFAOYSA-M 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- RCOSUMRTSQULBK-UHFFFAOYSA-N sodium;propan-1-olate Chemical compound [Na+].CCC[O-] RCOSUMRTSQULBK-UHFFFAOYSA-N 0.000 description 1
- 230000003381 solubilizing effect Effects 0.000 description 1
- 238000003797 solvolysis reaction Methods 0.000 description 1
- 239000008347 soybean phospholipid Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000002798 spectrophotometry method Methods 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 125000004079 stearyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 201000011549 stomach cancer Diseases 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 229940086735 succinate Drugs 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 150000003871 sulfonates Chemical class 0.000 description 1
- 229940071103 sulfosalicylate Drugs 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 229960001603 tamoxifen Drugs 0.000 description 1
- 229960001674 tegafur Drugs 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
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
- NRUKOCRGYNPUPR-QBPJDGROSA-N teniposide 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](OC[C@H]4O3)C=3SC=CC=3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 NRUKOCRGYNPUPR-QBPJDGROSA-N 0.000 description 1
- 229960001278 teniposide Drugs 0.000 description 1
- PSERLGWKMLMYNU-UHFFFAOYSA-N tetradeca-8,10,12-trien-6-yl acetate Chemical compound CCCCCC(OC(C)=O)CC=CC=CC=CC PSERLGWKMLMYNU-UHFFFAOYSA-N 0.000 description 1
- 150000003530 tetrahydroquinolines Chemical class 0.000 description 1
- 229960004559 theobromine Drugs 0.000 description 1
- 238000011287 therapeutic dose Methods 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- 229940100611 topical cream Drugs 0.000 description 1
- 229940100615 topical ointment Drugs 0.000 description 1
- UCFGDBYHRUNTLO-QHCPKHFHSA-N topotecan Chemical compound C1=C(O)C(CN(C)C)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 UCFGDBYHRUNTLO-QHCPKHFHSA-N 0.000 description 1
- 229960000303 topotecan Drugs 0.000 description 1
- XFCLJVABOIYOMF-QPLCGJKRSA-N toremifene Chemical compound C1=CC(OCCN(C)C)=CC=C1C(\C=1C=CC=CC=1)=C(\CCCl)C1=CC=CC=C1 XFCLJVABOIYOMF-QPLCGJKRSA-N 0.000 description 1
- 229960005026 toremifene Drugs 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 230000014616 translation Effects 0.000 description 1
- 229960000575 trastuzumab Drugs 0.000 description 1
- 229960001727 tretinoin Drugs 0.000 description 1
- 229960005526 triapine Drugs 0.000 description 1
- UBOXGVDOUJQMTN-UHFFFAOYSA-N trichloroethylene Natural products ClCC(Cl)Cl UBOXGVDOUJQMTN-UHFFFAOYSA-N 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
- 229960001099 trimetrexate Drugs 0.000 description 1
- NOYPYLRCIDNJJB-UHFFFAOYSA-N trimetrexate Chemical compound COC1=C(OC)C(OC)=CC(NCC=2C(=C3C(N)=NC(N)=NC3=CC=2)C)=C1 NOYPYLRCIDNJJB-UHFFFAOYSA-N 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 229960000875 trofosfamide Drugs 0.000 description 1
- UMKFEPPTGMDVMI-UHFFFAOYSA-N trofosfamide Chemical compound ClCCN(CCCl)P1(=O)OCCCN1CCCl UMKFEPPTGMDVMI-UHFFFAOYSA-N 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- RXRGZNYSEHTMHC-BQBZGAKWSA-N troxacitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1O[C@@H](CO)OC1 RXRGZNYSEHTMHC-BQBZGAKWSA-N 0.000 description 1
- 229950010147 troxacitabine Drugs 0.000 description 1
- 239000003744 tubulin modulator Substances 0.000 description 1
- 230000005740 tumor formation Effects 0.000 description 1
- 102000003390 tumor necrosis factor Human genes 0.000 description 1
- 229910052721 tungsten Inorganic materials 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- 230000003827 upregulation Effects 0.000 description 1
- 238000007738 vacuum evaporation Methods 0.000 description 1
- 229960000653 valrubicin Drugs 0.000 description 1
- ZOCKGBMQLCSHFP-KQRAQHLDSA-N valrubicin Chemical compound O([C@H]1C[C@](CC2=C(O)C=3C(=O)C4=CC=CC(OC)=C4C(=O)C=3C(O)=C21)(O)C(=O)COC(=O)CCCC)[C@H]1C[C@H](NC(=O)C(F)(F)F)[C@H](O)[C@H](C)O1 ZOCKGBMQLCSHFP-KQRAQHLDSA-N 0.000 description 1
- 230000035899 viability Effects 0.000 description 1
- 229960005212 vindesine sulfate Drugs 0.000 description 1
- NMDYYWFGPIMTKO-HBVLKOHWSA-N vinflunine Chemical compound C([C@@](C1=C(C2=CC=CC=C2N1)C1)(C2=C(OC)C=C3N(C)[C@@H]4[C@@]5(C3=C2)CCN2CC=C[C@]([C@@H]52)([C@H]([C@]4(O)C(=O)OC)OC(C)=O)CC)C(=O)OC)[C@H]2C[C@@H](C(C)(F)F)CN1C2 NMDYYWFGPIMTKO-HBVLKOHWSA-N 0.000 description 1
- 229960000922 vinflunine Drugs 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
- 230000029663 wound healing Effects 0.000 description 1
- 239000000230 xanthan gum Substances 0.000 description 1
- 235000010493 xanthan gum Nutrition 0.000 description 1
- 229920001285 xanthan gum Polymers 0.000 description 1
- 229940082509 xanthan gum Drugs 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229960000641 zorubicin Drugs 0.000 description 1
- FBTUMDXHSRTGRV-ALTNURHMSA-N zorubicin 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)=N\NC(=O)C=1C=CC=CC=1)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 FBTUMDXHSRTGRV-ALTNURHMSA-N 0.000 description 1
- VLCYCQAOQCDTCN-ZCFIWIBFSA-N α-difluoromethylornithine Chemical compound NCCC[C@@](N)(C(F)F)C(O)=O VLCYCQAOQCDTCN-ZCFIWIBFSA-N 0.000 description 1
- 229930195724 β-lactose Natural products 0.000 description 1
- PAPBSGBWRJIAAV-UHFFFAOYSA-N ε-Caprolactone Chemical compound O=C1CCCCCO1 PAPBSGBWRJIAAV-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/08—Bridged systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/38—Nitrogen atoms
- C07D215/42—Nitrogen atoms attached in position 4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
- C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
- C07D221/04—Ortho- or peri-condensed ring systems
- C07D221/06—Ring systems of three rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
Abstract
に関し、腫物の治療において使用することができる。
Description
本発明は、有用な特性、特に薬剤の調製で使用可能な特性を有する新規化合物を見出すことを目的とした。
本発明は、式Iの化合物
Wは、CHまたはNを表し、
R1、R2、R3は、相互に独立して、H、A、アリール、ヘテロアリール、Hal、−(CY2)n−SA、−(CY2)n−SCF3、−(CY2)n−SCN、−(CY2)n−CF3、−(CY2)n−OCF3、シクロアルキル、−SCH3、−SCN、−CF3、−OCF3、−OA、−(CY2)n−OH、−(CY2)n−CO2R、−(CY2)n−CN、−(CY2)n−Hal、(CH2)nR、−(CY2)n−NR2、(CY2)n−OR、(CY2)n−OCOA、−SCF3、(CY2)n−CONR2、−(CY2)n−NHCOA、−(CY2)n−NHSO2A、SF5、Si(CH3)3、CO−(CY2)n−CH3、−(CY2)n−N−ピロリドン、(CH2)nNRCOOR、NRCOOR、NCO、CH2(CH2)nCOOR、NHCOOR、CH2(CH2)nOH、NR(CH2)nOH、CH2NH2、(CH2)nNR2、CH(OH)R2、CH2NHCOR、(CH2)n−アリール、CH2(CH2)n−ヘテロアリール、(CH2)nR1、NH(CH2)nCOOR、CH2(CH2)nX(CH2)n−アリール、CH2(CH2)nX(CH2)n−ヘテロアリール、NH(CH2)nCONR2、XCONR(CH2)nNR2、N[(CH2)nXCOOR]CO(CH2)n−アリール、N[(CH2)nXR]CO(CH2)n−アリール、N[(CH2)nXR]CO(CH2)nX−アリール、N[(CH2)nXR]SO2(CH2)n−アリール、N[(CH2)nNRCOOR]CO(CH2)n−アリール、N[(CH2)nNR2]CO(CH2)n−アリール、N[(CH2)nNR2]CO(CH2)nNR−アリール、N[(CH2)nNR2]SO2(CH2)n−アリール、N[(CH2)nXR]CO(CH2)n−ヘテロアリール、N[(CH2)nXR]CO(CH2)nX−ヘテロアリール、N[(CH2)nXR]SO2(CH2)n−ヘテロアリール、N[(CH2)nNRCOOR]CO(CH2)n−ヘテロアリール、N[(CH2)nNR2]CO(CH2)n−ヘテロアリール、N[(CH2)nNR2]CO(CH2)nNR−ヘテロアリールを表し、
ここで、隣接していないCY2基はXで置換されていてもよく、R1およびR3は、一緒になって−N−C(CF3)=N−、−N−CR=N−、−N−N=N−をも表し、
Yは、H、A、Hal、OR1、N(R1)2、E−R1を表し、
Aは、1個または複数のH原子がHalで置換されていてもよいアルキルまたはシクロアルキルを表し、かつ/または、1個または複数の隣接していないCH2基はXで置換されていてもよく、
Halは、F、Cl、BrまたはIを表し、
Rは、HまたはAを表し、ジェミナル基のRは、一緒になって−(CH2)5−、−(CH2)4−もしくは−(CH2)n−X−(CH2)n、または−(CH2)n−Z−(CH2)nをも表し、
R4は、Hを表し、
R5は、相互に独立して、Hまたは非置換またはモノ−またはポリ−OR−、−NO2−、−Hal−、−CF3−、−OCF3−、−CN−、−NR2−または−SR−、−アリール−または−ヘテロアリール−置換N−ピロリドン、−X−(CH2)2OR、−X−CO(CH2)nCH3、−X−(CH2)2NR2、R1、S−アリール、O−アリール、CH2Si(CH3)3、Q、−(CY2)n−E−CR2R1、−(CY2)n−E−CR2XR1、−(CY2)n−E−(CY2)n−XR1または−(CY2)n−E−(CY2)n−XRaを表し、
Eは、−NR1SO2−、−SO2NR1−、−CONR1−、−NR1CO−、−COO−、−OOC−、NR1CONR1−、−OCONR1−、−NR1COO−、−CSNR1−、−NR1CS−、−NR1CSNR1−、−SCONR1−、−NR1COS−、−OCSNR1−、NR1CSO−、SCSNR1−、−NR1CSSまたは単結合を表し、
Xは、O、SまたはNR1を表し、
Qは、(CH2)pHal、CHO、CORa、(CH2)pRa、(CH2)pOCORa、(CH2)pXR1、(CH2)pNCOR1、(CH2)pN(R1)2、(CH2)pOR1、(CH2)pOCON(R1)2、(CH2)pOCOOR1、(CH2)pNHCON(R1)2、(CH2)pNHCOOR1、(CH2)pCN、(CH2)pCOOR1、(CH2)p−E−(CH2)pR1、(CH2)p−E−(CH2)pRaを表し、ここで、隣接していないCH2基はXで置換されていてもよく、
Raは、
Zは、CH2、X、CHCONH2、CH(CH2)nNR1COOR1、CHNR1COOR1、CHCON(R1)2、NCO、CH(CH2)nCOOR1、NCOOR1、CH(CH2)nOH、N(CH2)nOH、CHNH2、CH(CH2)nN(R1)2、CH(CH2)nN(R1)2、C(OH)R1、CHNCOR1、NCOR1、N(CH2)n−アリール、N(CH2)n−ヘテロアリール、CHR1、NR1、CH(CH2)n−アリール、CH(CH2)n−ヘテロアリール、CH(CH2)nR1、N(CH2)nCOOR1、CH(CH2)nX(CH2)nR1、CH(CH2)nX(CH2)nRa、N(CH2)nCON(R1)2、XCONR1(CH2)nN(R1)2、CO(CH2)nR1、CO(CH2)nR1、CO(CH2)nXR1、SO2(CH2)nR1、O(CH2)nN(R1)2、X(CH2)nN(R1)2、NCO(CH2)nN(R1)2、CHRa、NRaを表し、
R6は、それぞれ非置換の、あるいはそれぞれ(Hal、NO2、CN、A、OR、OCOR、COR、NR2、CF3、OCF3、OCH(CF3)2)で置換されてもよい)アリールもしくはヘテロアリールで、またはHal、NO2、CN、OR、A、−(CY2)n−OR、−OCOR、−(CY2)n−CO2R、−(CY2)−CN、−NCOR、−CORもしくは−(CY2)n−NR2で一置換もしくは多置換されている、アリールあるいはヘテロアリールを表し、
R7は、(C=O)−R、(C=O)−NR2、(C=O)−OR、HまたはAを表し、ここで、R5およびR7は、一緒になって−(CH2)n−を表していてもよく、
mは、0、1または2を表し、
nは、0、1、2、3、4、5、6または7を表し、
pは、0、1、2、3、4、または5を表し、好ましくは2または3を表し、
Sは、0、1、2、3、4、5、6または7を表し、好ましくは0を表す)
ならびにそれらの薬学的に利用可能な誘導体、溶媒和物、互変異性体、塩および立体異性体、ならびにそれらのあらゆる割合の混合物に関する。
プロドラッグ誘導体という用語は、例えば、アルキル基またはアシル基、糖またはオリゴペプチドによって修飾されており、生物内で速やかに開裂されて本発明による有効な化合物を形成する式Iの化合物を意味するものとする。
これらには、例えば、Int.J.Pharm.115、61〜67(1995)に記載のような、本発明による化合物の生分解性高分子誘導体も含まれる。
さらに「治療有効量」という用語には、正常な生理学的機能の増強または強化に有効な量も包含される。
MsCl=メタンスルホニルクロライド
(式中、R1は上述の意味を有し、sは、好ましくは0、1または2を表し、特に1を表す。)
上記の方法により得ることができる式Iの化合物のジアステレオマーおよび鏡像異性体の混合物は、クロマトグラフィーまたは結晶化によって好ましくは分離する。
Aは、特に好ましくは、1、2、3、4、5または6個のC原子を有するアルキル、好ましくはメチル、エチル、プロピル、イソプロピル、ブチル、イソブチル、sec−ブチル、tert−ブチル、ペンチル、ヘキシル、トリフルオロメチル、ペンタフルオロエチルまたは1,1,1−トリフルオロエチルを表す。またAは、シクロアルキルも表す。
シクロアルキルは、好ましくは、シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシルまたはシクロヘプチル、特にシクロペンチルを表す。
−(CH2)n−E−R1、−(CH2)nX(CH2)n−E−R1、−(CY2)n−E−(CY2)n−XR1、−(CY2)n−E−R1、(CH2)nCH(OH)−E−R1
(式中、X、R1、E、Y、nおよびRaは、上述の意味を有する)
のうちの1つを表す。
(CH2)2OH、(CH2)3OH、(CH2)2NRR1、(CH2)3NRR1、(CH2)2CH(OH)CH2OH、(CH2)2CH(OH)CH2NRR1、(CH2)2CH(OH)CH2NR(CH2)2NRR1、(CH2)2CH(OH)CH2NR5(CH2)2NR、(CH2)2CH(OH)CH2−E−R1、Q、(CH2)2CH(OH)CH2NR(CH2)2OR、(CH2)3NHMe、(CH2)3OCOCH3、(CH2)3OH、(CH2)3CON(CH2)2NMe2、(CH2)3NSO2(CH2)3NHCH3。
(式中、R、R1、EおよびQは、上述の意味を有する)
の1つを有する。
の1つを表す。
アリールは、好ましくは、フェニル、o−、m−またはp−トリル、o−、m−またはp−エチルフェニル、o−、m−またはp−プロピルフェニル、o−、m−またはp−イソプロピルフェニル、o−、m−またはp−tert−ブチルフェニル、o−、m−またはp−ヒドロキシフェニル、o−、m−またはp−メトキシフェニル、o−、m−またはp−ニトロフェニル、o−、m−またはp−アミノフェニル、o−、m−またはp−(N−メチルアミノ)フェニル、o−、m−またはp−(N−メチルアミノカルボニル)フェニル、o−、m−またはp−アセトアミドフェニル、o−、m−またはp−メトキシフェニル、o−、m−またはp−エトキシフェニル、o−、m−またはp−エトキシカルボニルフェニル、o−、m−またはp−(N,N−ジメチルアミノ)フェニル、o−、m−またはp−(N,N−ジメチルアミノカルボニル)フェニル、o−、m−またはp−(N−エチルアミノ)フェニル、o−、m−またはp−(N,N−ジエチルアミノ)フェニル、o−、m−またはp−フルオロフェニル、o−、m−またはp−ブロモフェニル、o−、m−またはp−クロロフェニル、o−、m−またはp−(メチルスルホンアミド)フェニル、o−、m−またはp−(メチルスルホニル)フェニル、さらに好ましくは2,3−、2,4−、2,5−、2,6−、3,4−または3,5−ジフルオロフェニル、2,3−、2,4−、2,5−、2,6−、3,4−または3,5−ジクロロフェニル、2,3−、2,4−、2,5−、2,6−、3,4−または3,5−ジブロモフェニル、2,4−または2,5−ジニトロフェニル、2,5−または3,4−ジメトキシフェニル、3−ニトロ−4−クロロフェニル、3−アミノ−4−クロロ−、2−アミノ−3−クロロ−、2−アミノ−4−クロロ−、2−アミノ−5−クロロ−または2−アミノ−6−クロロフェニル、2−ニトロ−4−N,N−ジメチルアミノ−または3−ニトロ−4−N,N−ジメチルアミノフェニル、2,3−ジアミノフェニル、2,3,4−、2,3,5−、2,3,6−、2,4,6−または3,4,5−トリクロロフェニル、2,4,6−トリメトキシフェニル、2−ヒドロキシ−3,5−ジクロロフェニル、p−ヨードフェニル、3,6−ジクロロ−4−アミノフェニル、4−フルオロ−3−クロロフェニル、2−フルオロ−4−ブロモフェニル、2,5−ジフルオロ−4−ブロモフェニル、3−ブロモ−6−メトキシフェニル、3−クロロ−6−メトキシフェニル、3−クロロ−4−アセトアミドフェニル、3−フルオロ−4−メトキシフェニル、3−アミノ−6−メチルフェニル、3−クロロ−4−アセトアミドフェニルまたは2,5−ジメチル−4−クロロフェニルを表す。
およびそのラセミ体または鏡像異性体の他の混合物である。式IAの化合物が特に好ましい。
である。
処方に従って調製される注射溶液および懸濁液は、滅菌した粉末、顆粒および錠剤から調製することができる。
(a)式Iの化合物ならびに/またはその薬学的に利用可能な誘導体、溶媒和物、立体異性体、およびあらゆる割合でのそれらの混合物の有効量と、
(b)さらなる薬剤有効成分の有効量と
からなるセット(キット)にも関する。
「エストロゲン受容体モジュレーター」は、機序に関係なくエストロゲンの受容体への結合を妨害または阻害する化合物を意味する。エストロゲン受容体モジュレーターの例としては、タモキシフェン、ラロキシフェン、イドキシフェン、LY353381、LY117081、トレミフェン、フルベストラント、4−[7−(2,2−ジメチル−1−オキソプロポキシ−4−メチル−2−[4−[2−(1−ピペリジニル)−エトキシ]フェニル]−2H−1−ベンゾピラン−3−イル]フェニル2,2−ジメチルプロパノエート、4,4’−ジヒドロキシベンゾフェノン−2,4−ジニトロフェニルヒドラゾンおよびSH646が挙げられるが、これらに限定されるものではない。
「アンドロゲン受容体モジュレーター」は、機序に関係なくアンドロゲンの受容体への結合を妨害または阻害する化合物を意味する。アンドロゲン受容体モジュレーターの例としては、フィナステリドおよび他の5α−還元酵素阻害剤であるニルタミド、フルタミド、ビカルタミド、リアロゾールおよび酢酸アビラテロンが挙げられる。
「レチノイド受容体モジュレーター」は、機序に関係なくレチノイドの受容体への結合を妨害または阻害する化合物を意味する。かかるレチノイド受容体モジュレーターの例としては、ベキサロテン、トレチノイン、13−シス−レチノイン酸、9−シス−レチノイン酸、α−ジフルオロメチルオルニチン、ILX23−7553、トランス−N−(4’−ヒドロキシフェニル)レチンアミドおよびN−4−カルボキシフェニルレチンアミドが挙げられる。
「細胞毒性薬」は、主として細胞機能への直接作用を介して細胞死をもたらすか、または細胞分裂を阻害もしくは妨害する化合物を意味し、それにはアルキル化剤、腫瘍壊死因子、インターカレーター、ミクロチューブリン阻害剤およびトポイソメラーゼ阻害剤が含まれる。
細胞毒性薬の例としては、チラパジミン(tirapazimine)、セルテネフ、カケクチン、イホスファミド、タソネルミン、ロニダミン、カルボプラチン、アルトレタミン、プレドニムスチン、ジブロモズルシトール(dibromodulcitol)、ラニムスチン、フォテムスチン、ネダプラチン、オキサリプラチン、テモゾロミド、ヘプタプラチン(heptaplatin)、エストラムスチン、トシル酸インプロスルファン、トロホスファミド、ニムスチン、塩化ジブロスピジウム、プミテパ、ロバプラチン、サトラプラチン、プロフィロマイシン(profiromycin)、シスプラチン、イロフルベン、デキシフォスファミド(dexifosfamide)、シス−アミンジクロロ(2−メチルピリジン)白金、ベンジルグアニン、グルフォスファミド、GPX100、(トランス,トランス,トランス)ビス−μ−(ヘキサン−1,6−ジアミン)μ−[ジアミン白金(II)]ビス[ジアミン(クロロ)白金(II)]テトラクロリド、ジアリシジニルスペルミン(diarizidinylspermine)、三酸化ヒ素、1−(11−ドデシルアミノ−10−ヒドロキシウンデシル)−3,7−ジメチルキサンチン、ゾルビシン、イダルビシン、ダウノルビシン、ビサントレン、ミトキサントロン、ピラルビシン、ピナフィド、バルルビシン、アムルビシン、アンチネオプラストン、3’−デアミノ−3’−モルホリノ−13−デオキソ−10−ヒドロキシカルミノマイシン、アナマイシン、ガラルビシン、エリナフィド、MEN10755および4−デメトキシ−3−デアミノ−3−アジリジニル−4−メチルスルホニルダウノルビシン(WO 00/50032を参照)が挙げられるが、これらに限定されるものではない。
ミクロチューブリン阻害剤の例としては、パクリタキセル、硫酸ビンデシン、3’,4’−ジデヒドロ−4’−デオキシ−8’−ノルビンカロイコブラスチン(norvincaleukoblastine)、ドセタキソール、リゾキシン、ドラスタチン、イセチオン酸ミボブリン、オーリスタチン、セマドチン、RPR109881、BMS184476、ビンフルニン、クリプトフィシン、2,3,4,5,6−ペンタフルオロ−N−(3−フルオロ−4−メトキシフェニル)ベンゼンスルホンアミド、アンヒドロビンブラスチン、N,N−ジメチル−L−バリル−L−バリル−N−メチル−L−バリル−L−プロリル−L−プロリン−t−ブチルアミド、TDX258およびBMS188797が挙げられる。
トポイソメラーゼ阻害剤の一部の例としては、トポテカン、ヒカプタミン(hycaptamine)、イリノテカン、ルビテカン、6−エトキシプロピオニル−3’,4’−O−エキソベンジリデンチャルトレウシン、9−メトキシ−N,N−ジメチル−5−ニトロピラゾロ[3,4,5−kl]アクリジン−2−(6H)プロパンアミン、1−アミノ−9−エチル−5−フルオロ−2,3−ジヒドロ−9−ヒドロキシ−4−メチル−1H,12H−ベンゾ[de]ピラノ[3’,4’:b,7]インドリジノ[1,2b]キノリン−10,13(9H,15H)ジオン、ルルトテカン(lurtotecan)、7−[2−(N−イソプロピルアミノ)エチル]−(20S)カンプトテシン、BNP1350、BNPI1100、BN80915、BN80942、リン酸エトポシド、テニポシド、ソブゾキサン、2’−ジメチルアミノ−2’−デオキシエトポシド、GL331、N−[2−(ジメチルアミノ)−エチル]−9−ヒドロキシ−5,6−ジメチル−6H−ピリド[4,3−b]カルバゾール−1−カルボキサミド、アスラクリン(asulacrine)、(5a,5aB,8aa,9b)−9−[2−[N−[2−(ジメチルアミノ)エチル]−N−メチルアミノ]エチル]−5−[4−ヒドロキシ−3,5−ジメトキシフェニル]−5,5a,6,8,8a,9−ヘキソ−ヒドロフロ(3’,4’:6,7)ナフト(2,3−d)−1,3−ジオキソール−6−オン、2,3−(メチレンジオキシ)−5−メチル−7−ヒドロキシ−8−メトキシベンゾ[c]フェナントリジニウム、6,9−ビス[(2−アミノエチル)アミノ]ベンゾ[g]イソキノリン−5,10−ジオン、5−(3−アミノプロピルアミノ)−7,10−ジヒドロキシ−2−(2−ヒドロキシエチルアミノメチル)−6H−ピラゾロ[4,5,1−de]アクリジン−6−オン、N−[1−[2(ジエチルアミノ)エチルアミノ]−7−メトキシ−9−オキソ−9H−チオキサンテン−4−イルメチル]ホルムアミド、N−(2−(ジメチルアミノ)エチル)アクリジン−4−カルボキサミド、6−[[2−(ジメチルアミノ)エチル]アミノ]−3−ヒドロキシ−7H−インデノ[2,1−c]キノリン−7−オンおよびジメスナである。
「抗増殖剤」としては、G3139、ODN698、RVASKRAS、GEM231およびINX3001などのアンチセンスRNAおよびDNAオリゴヌクレオチド、ならびにエノシタビン、カルモフール、テガフール、ペントスタチン、ドキシフルリジン、トリメトレキサート、フルダラビン、カペシタビン、ガロシタビン、シタラビンオクホスフェート、フォステアビン(fosteabine)ナトリウム水和物、ラルチトレキセド、パルチトレキシド(paltitrexid)、エミテフル、チアゾフリン、デシタビン、ノラトレキセド、ペメトレキセド、ネルザラビン、2’−デオキシ−2’−メチリデンシチジン、2’−フルオロメチレン−2’−デオキシシチジン、N−[5−(2,3−ジヒドロベンゾフリル)スルホニル]−N’−(3,4−ジクロロフェニル)尿素、N6−[4−デオキシ−4−[N2−[2(E),4(E)−テトラデカジエノイル]グリシルアミノ]−L−グリセロ−B−L−マンノヘプトピラノシル]アデニン、アプリジン、エクテイナシジン、トロキサシタビン、4−[2−アミノ−4−オキソ−4,6,7,8−テトラヒドロ−3H−ピリミジノ[5,4−b]−1,4−チアジン−6−イル−(S)−エチル]−2,5−チエノイル−L−グルタミン酸、アミノプテリン、5−フルオロウラシル、アラノシン、11−アセチル−8−(カルバモイルオキシメチル)−4−ホルミル−6−メトキシ−14−オキサ−1,11−ジアザテトラシクロ(7.4.1.0.0)テトラデカ−2,4,6−トリエン−9−イル酢酸エステル、スワインソニン、ロメトレキソール、デキスラゾキサン、メチオニナーゼ、2’−シアノ−2’−デオキシ−N4−パルミトイル−1−B−D−アラビノフラノシルシトシンおよび3−アミノピリジン−2−カルボキシアルデヒドチオセミカルバゾンなどの代謝拮抗物質が挙げられる。また「抗増殖剤」としては、トラスツズマブなどの「血管新生阻害剤」の項目で挙げた以外の増殖因子に対するモノクローナル抗体、および組換えウイルス介在性遺伝子導入により送達できるp53などの癌抑制遺伝子も挙げられる(例えば、米国特許第6,069,134号を参照)。
a)1種または複数の式Iの化合物、および
b)1種または複数の式Vの化合物またはその酸付加塩、特に塩酸塩:
の投与による、癌などの新生物のある患者を治療するための方法も包含し、その場合、第1化合物および第2化合物は、同時にまたは相互に14日以内にその新生物の増殖を阻害するのに十分な量で投与される。
・ペンタミジンとさらに式Iの化合物の両方が細胞を細胞周期G2/M期に維持する、
・ペンタミジンと式Iの化合物との組み合わせは、細胞増殖に相加作用ないし相乗作用を有する。
,5−ビス[4−(N−フェノキシカルボニル)アミジノフェニル]フラン、2,5−ビス[4−(N−(4−フルオロ)−フェノキシカルボニル)アミジノフェニル]フラン、2,5−ビス[4−(N−(4−メトキシ)フェノキシカルボニル)アミジノフェニル]フラン、2,5−ビス[4−(1−アセトキシエトキシカルボニル)アミジノフェニル]フランおよび2,5−ビス[4−(N−(3−フルオロ)フェノキシカルボニル)アミジノフェニル]−フランが挙げられる。上記化合物の1つを調製する方法は、米国特許第5,428,051号、第5,521,189号、第5,602,172号、第5,643,935号、第5,723,495号、第5,843,980号、第6,172,104号および第6,326,395号または公開番号がUS 2002/0019437 A1の米国特許出願に記載されている。
(4a,10,10a)−6−tert−ブチル−10−フェニル−2,3,4a,9,10,10a−ヘキサヒドロ−1,4−ジオキサ−9−アザフェナントレンの合成
a.3−[6−tert−ブチル−3−(3−ヒドロキシプロピル)キノリン−2−イル]フェノール(1)の合成
アセトニトリル500ml中に4−tert−ブチルアニリン99.0g(663mmol)を溶解し、氷冷しながらトリフルオロ酢酸51.6ml(670mmol)を添加した。最初に、アセトニトリル500mlに溶解した3,4−ジヒドロ−2H−ピラン46.4g(670mmol)および3−ヒドロキシベンズアルデヒド81.8g(670mmol)の溶液を第2のフラスコに氷冷しながら入れた。この反応溶液に、5℃まで予冷却したアニリントリフルオロ酢酸塩を速やかに添加し、この温度で撹拌を約2時間続けた。反応混合物を蒸発させ、残渣を水2Lに懸濁させ、水酸化ナトリウム溶液を用いてpHを12に調整した。形成されたエマルジョンをtert−ブチルメチルエーテル1Lで2回抽出した。有機相をNA2SO4で乾燥させ、一晩4℃で結晶化させた。沈澱した無色の生成物1を濾過し、乾燥させたところ、無色の結晶体6.00が得られた。DE10360154.6に記載のようにして、3−(9−tert−ブチル−3,4,4a,5,6,10b−ヘキサヒドロ−2H−ピラノ−[3,2−c]キノリン−5−イル)フェノールを濾液から分離し、さらにこれをcの項目で記載したように化合物1まで変換した。
5.00g(14.9mmol)の1を無水エタノール(60ml)に溶解し、加熱還流した。沸騰しているその溶液にナトリウム6.00g(0.23mol、17.5eq)を30〜60分かけて少量ずつ添加し、添加終了後、撹拌を還流下で2時間継続した。氷水を冷却溶液に慎重に添加し、pH値が中性になるまでNaHCO3を加え、混合物を酢酸エチルで2回抽出した。集めた有機相を乾燥させ、蒸発乾固した。カラムクロマトグラフイー(酢酸エチル/シクロヘキサン)によって精製を行なったところ、同重量の2画分が分離された。これらは無色の固体であり、トランス形2aおよびシス形2bの化合物として同定された。
5−フェニル−9−トリフルオロメチル−3,4,4a,5,6,10b−ヘキサヒドロ−2H−ピラノ[3,2−c]キノリン(3)0.50g(1.50mmol)をTHF(15ml)中に溶解し、セリウム(IV)硝酸アンモニウム1.65g(3.00mmol、2eq)を室温で添加し、一晩室温で撹拌を続けた。反応終了後、酢酸エチル50mlを添加し、混合物を水50mlで2回抽出した。有機相を乾燥させ、蒸発乾固した。残渣を酢酸エチル/ジエチルエーテルから再結晶化させたところ、淡黄色の固体(化合物4)が得られた。
0.44g(1.33mmol)の4をメタノール15ml中に取り、ラネーニッケル(湿潤)1gを添加し、混合物を60℃で5barの水素圧力下にて一晩水素化した。触媒を分離した後、さらにラネーニッケル1gを加え、混合物を60℃で5barの水素圧力下にて一晩水素化した。触媒を濾過した後、濾液を蒸発乾固し、残渣をカラムクロマトグラフイー(MeOH/酢酸エチル)で精製したところ、無色の固体が得られた。これはラセミ化合物5として同定された。
cの項目で記載したように、1.00g(3.58mmol)の6を、THF(30ml)に溶解したセリウム(IV)硝酸アンモニウム3.92g(7.16mmol、2eq)と反応させたところ、帯黄色の固体として化合物7が得られた。
b)の項目で記載したように、0.80g(2.88mmol)の7を、EtOH(10ml)に溶解したナトリウム0.66g(28.8mmol、10eq)と反応させたところ、無色の固体としての化合物トランス形8と、同じく無色の固体としての化合物シス形8が得られた。
DCM(2ml)に0.10g(0.36mmol)のトランス形8を溶解し、最初に、1mlのDCMに溶解したトリエチルアミン76mg(0.75、2.1eq)および塩化メタンスルホニル50mg(0.43mmol、1.2eq)を室温で加え、混合物を同じ温度でさらに30分間撹拌した。混合物を蒸発乾固し、酢酸エチル中に取り、水で2回洗浄した。有機相を乾燥させ、蒸発乾固し、それ以上精製を行うことなくさらに反応させたところ、無色の油状物が得られたが、これは一晩で結晶化した(化合物9)。
0.10g(0.28mmol)の9をイソプロピルアミン(0.2ml)に溶解させ、圧力フラスコ中100℃で18時間加熱した。過剰のアミンを真空蒸着によって除去し、残渣を酢酸エチル中に取り、水で抽出した。有機相を乾燥させ、蒸発乾固し、残渣にiPrOHに溶解した過剰のHClとジエチルエーテルを加えた。結晶固体を濾過し、乾燥させたところ、無色の固体(一塩酸塩としての化合物10)が得られた。一部においては、化合物8が副生成物として再形成されたため、この段階でカラムクロマト精製を選択しなければならなかった。
2−アミノ−5−メチルベンズアルデヒド11 2.00g(14.6mmol)(2−アミノ−5−メチルベンジルアルコール2g(14.6mmol)と二酸化マンガン6.52g(75.0mmol)とをDMF50ml中で室温にて3時間反応させ、続いてセライトを通過させて濾過し、溶媒を蒸発させることにより得られたもの)および3−ベンゾイルプロピオン酸12 2.60g(14.6mmol)をMeOH(40ml)に取り、水に溶解した2NのNaOH溶液10mlを室温で添加し、その混合物を18時間加熱還流した。混合物を水15mlで希釈し、pHが酸性領域に変化するまで酢酸を加えた。形成された沈殿物を濾過し、乾燥させた。得られた無色の固体は、高純度の所望の生成物13として同定された。
メタノール80mlに1.00g(3.61mmol)の13を取り、ラネーニッケル(湿潤)1gを加え、その混合物を50℃で5barの水素圧力下にて一晩水素化した。触媒を濾過し、濾液を蒸発乾固し、残渣をカラムクロマトグラフイー(酢酸エチル/シクロヘキサン)により精製したところ、帯黄色の固体が得られた。これはラセミ型の化合物シス形14であると同定された。
DMF1mlに溶解した100mg(0.36mmol)の14およびジエチルアミン50ml(0.49mmol、1.4eq)を最初に入れ、1−ヒドロキシ−ベンゾトリアゾール50mg(0.37mmol)、N−(3−ジメチルアミノプロピル)−N’−エチル−塩酸カルボジイミド140mg(0.73mmol)ならびに4−メチルモルホリン80ml(0.73mmol)を室温で撹拌しながら添加した。続いて、反応混合物を室温で2時間撹拌した。この混合物にtert−ブチルメチルエーテルを加え、次いで水で2回抽出した。有機相を乾燥、蒸発させ、残渣をカラムクロマトグラフイー(酢酸エチル/シクロヘキサン)により精製したところ、無色の固体が得られ、これは化合物15と同定された。
I.(6−メチル−2−フェニルキノリン−3−イル)酢酸エチル(16)の合成
EtOH(10ml)に0.50g(1.80mmol)の13を溶解し、濃硫酸1滴を加え、混合物を2時間加熱還流した。溶媒を除去し、残渣を酢酸エチルに取り、水で2回洗浄した。有機相を乾燥、蒸発させた。無色油状物の残渣は化合物16である。
0.50g(1.64mmol)の16をTHF(5ml)に溶解し、これをTHF(10ml)に溶解した水素化アルミニウムリチウム(LiAIH4、粉末)0.12g(3.27mmol)の懸濁液に、氷冷し撹拌しながらゆっくりと滴下添加した。混合物を室温で3時間撹拌し、飽和塩化アンモニウム溶液を添加することにより過剰のLiAIH4を粉砕し、混合物を酢酸エチルで2回抽出した。合わせた有機相を乾燥させ、溶媒を除去し、残渣をカラムクロマトグラフイー(酢酸エチル/シクロヘキサン)によって精製したところ、無色の固体(化合物17)が得られた。この化合物は、f.g.およびh.の項目で記載のように、さらに反応させることができる。
本発明による化合物の有効性は、例えばEg5 ATPアーゼ活性によって決定できる。前記活性は、ピルビン酸キナーゼ(PK)およびそれに続いて起こるNADH依存性乳酸デヒドロゲナーゼ(LDH)反応とのカップリングによる、産物ADPからATPへの酵素的再生によって測定される。この反応は、NADH依存性LDHとのカップリングによる340nmでの吸光度の変化によってモニタリングできる。ATPの再生は、基質濃度が一定に保たれていることを同時に確認する。単位時間あたりの吸光度の変化をグラフから分析し、視覚的に反応が直線である領域で直線回帰を行う。
抗原虫剤ペンタミジンとキネシンATPアーゼEg5/KSPの阻害剤とを組み合わせると、結腸癌細胞系HCT116を用いた細胞増殖試験で阻害作用が増強される。
Eg5阻害剤はATPアーゼ活性に悪影響を及ぼし、紡錘極分離の障害により細胞周期の進行を阻害する。
実施例C:注射用バイアル
再蒸留水3Lに溶解した式Iの有効成分100gおよびリン酸一水素二ナトリウム5gの溶液を、2N塩酸を用いてpH6.5に調整し、濾過滅菌し、注射用バイアルに移し、無菌条件下で凍結乾燥して無菌条件下で密封する。各注射用バイアルは有効成分5mgを含有する。
式Iの有効成分20gと、ダイズレシチン100gおよびカカオバター1400gとの混合物を融解させ、型に注いで冷却する。各坐剤は有効成分20mgを含有する。
再蒸留水940mlに式Iの有効成分1g、NaH2PO4・2H2Oを9.38g、Na2HPO4・12H2Oを28.48g、および塩化ベンザルコニウム0.1gを溶解した溶液を調製する。pHを6.8に調整し、溶液を1Lとし、照射滅菌する。この溶液は点眼剤の形態で使用できる。
無菌条件下で式Iの有効成分500mgをワセリン99.5gと混合する。
式Iの有効成分1kg、ラクトース4kg、バレイショデンプン1.2kg、タルク0.2kgおよびステアリン酸マグネシウム0.1kgの混合物を従来法で圧縮し、各錠剤が有効成分10mgを含有するように錠剤を得る。
実施例Eと同様にして錠剤を圧縮し、続いて従来法でスクロース、バレイショデンプン、タルク、トラガカントゴムおよび色素のコーティングを被覆する。
式Iの有効成分2kgを従来法でゼラチン硬カプセルに導入し、各カプセルが有効成分20mgを含有するようにする。
再蒸留水60Lに溶解した式Iの有効成分1kgの溶液を濾過滅菌し、アンプルに移し、無菌条件下で凍結乾燥し、無菌条件下で密封する。各アンプルは有効成分10mgを含有する。
Claims (30)
- 式Iの化合物
(式中、
Wは、CHまたはNを表し、
R1、R2、R3は、相互に独立して、H、A、アリール、ヘテロアリール、Hal、−(CY2)n−SA、−(CY2)n−SCF3、−(CY2)n−SCN、−(CY2)n−CF3、−(CY2)n−OCF3、シクロアルキル、−SCH3、−SCN、−CF3、−OCF3、−OA、−(CY2)n−OH、−(CY2)n−CO2R、−(CY2)n−CN、−(CY2)n−Hal、(CH2)nR、−(CY2)n−NR2、(CY2)n−OR、(CY2)n−OCOA、−SCF3、(CY2)n−CONR2、−(CY2)n−NHCOA、−(CY2)n−NHSO2A、SF5、Si(CH3)3、CO−(CY2)n−CH3、−(CY2)n−N−ピロリドン、(CH2)nNRCOOR、NRCOOR、NCO、CH2(CH2)nCOOR、NHCOOR、CH2(CH2)nOH、NR(CH2)nOH、CH2NH2、(CH2)nNR2、CH(OH)R2、CH2NHCOR、(CH2)n−アリール、CH2(CH2)n−ヘテロアリール、(CH2)nR1、NH(CH2)nCOOR、CH2(CH2)nX(CH2)n−アリール、CH2(CH2)nX(CH2)n−ヘテロアリール、NH(CH2)nCONR2、XCONR(CH2)nNR2、N[(CH2)nXCOOR]CO(CH2)n−アリール、N[(CH2)nXR]CO(CH2)n−アリール、N[(CH2)nXR]CO(CH2)nX−アリール、N[(CH2)nXR]SO2(CH2)n−アリール、N[(CH2)nNRCOOR]CO(CH2)n−アリール、N[(CH2)nNR2]CO(CH2)n−アリール、N[(CH2)nNR2]CO(CH2)nNR−アリール、N[(CH2)nNR2]SO2(CH2)n−アリール、N[(CH2)nXR]CO(CH2)n−ヘテロアリール、N[(CH2)nXR]CO(CH2)nX−ヘテロアリール、N[(CH2)nXR]SO2(CH2)n−ヘテロアリール、N[(CH2)nNRCOOR]CO(CH2)n−ヘテロアリール、N[(CH2)nNR2]CO(CH2)n−ヘテロアリール、N[(CH2)nNR2]CO(CH2)nNR−ヘテロアリールを表し、
ここで、隣接していないCY2基はXで置換されていてもよく、R1およびR3は、一緒になって−N−C(CF3)=N−、−N−CR=N−、−N−N=N−をも表し、
Yは、H、A、Hal、OR1、N(R1)2、E−R1を表し、
Aは、1個または複数のH原子がHalで置換されていてもよいアルキルまたはシクロアルキルを表し、かつ/または、1個または複数の隣接していないCH2基はXで置換されていてもよく、
Halは、F、Cl、BrまたはIを表し、
Rは、HまたはAを表し、ジェミナル基のRは、一緒になって−(CH2)5−、−(CH2)4−もしくは−(CH2)n−X−(CH2)n、または−(CH2)n−Z−(CH2)nをも表し、
R4は、Hを表し、
R5は、相互に独立して、Hまたは非置換またはモノ−またはポリ−OR−、−NO2−、−Hal−、−CF3−、−OCF3−、−CN−、−NR2−または−SR−、−アリール−または−ヘテロアリール−置換N−ピロリドン、−X−(CH2)2OR、−X−CO(CH2)nCH3、−X−(CH2)2NR2、R1、S−アリール、O−アリール、CH2Si(CH3)3、Q、−(CY2)n−E−CR2R1、−(CY2)n−E−CR2XR1、−(CY2)n−E−(CY2)n−XR1または−(CY2)n−E−(CY2)n−XRaを表し、
Eは、−NR1SO2−、−SO2NR1−、−CONR1−、−NR1CO−、−COO−、−OOC−、NR1CONR1−、−OCONR1−、−NR1COO−、−CSNR1−、−NR1CS−、−NR1CSNR1−、−SCONR1−、−NR1COS−、−OCSNR1−、NR1CSO−、SCSNR1−、−NR1CSSまたは単結合を表し、
Xは、O、SまたはNR1を表し、
Qは、(CH2)pHal、CHO、CORa、(CH2)pRa、(CH2)pOCORa、(CH2)pXR1、(CH2)pNCOR1、(CH2)pN(R1)2、(CH2)pOR1、(CH2)pOCON(R1)2、(CH2)pOCOOR1、(CH2)pNHCON(R1)2、(CH2)pNHCOOR1、(CH2)pCN、(CH2)pCOOR1、(CH2)p−E−(CH2)pR1、(CH2)p−E−(CH2)pRaを表し、ここで、隣接していないCH2基はXで置換されていてもよく、
Raは、
Zは、CH2、X、CHCONH2、CH(CH2)nNR1COOR1、CHNR1COOR1、CHCON(R1)2、NCO、CH(CH2)nCOOR1、NCOOR1、CH(CH2)nOH、N(CH2)nOH、CHNH2、CH(CH2)nN(R1)2、CH(CH2)nN(R1)2、C(OH)R1、CHNCOR1、NCOR1、N(CH2)n−アリール、N(CH2)n−ヘテロアリール、CHR1、NR1、CH(CH2)n−アリール、CH(CH2)n−ヘテロアリール、CH(CH2)nR1、N(CH2)nCOOR1、CH(CH2)nX(CH2)nR1、CH(CH2)nX(CH2)nRa、N(CH2)nCON(R1)2、XCONR1(CH2)nN(R1)2、CO(CH2)nR1、CO(CH2)nR1、CO(CH2)nXR1、SO2(CH2)nR1、O(CH2)nN(R1)2、X(CH2)nN(R1)2、NCO(CH2)nN(R1)2、CHRa、NRaを表し、
R6は、それぞれ非置換の、あるいはそれぞれ(Hal、NO2、CN、A、OR、OCOR、COR、NR2、CF3、OCF3、OCH(CF3)2)で置換されてもよい)アリールもしくはヘテロアリールで、またはHal、NO2、CN、OR、A、−(CY2)n−OR、−OCOR、−(CY2)n−CO2R、−(CY2)−CN、−NCOR、−CORもしくは−(CY2)n−NR2で一置換もしくは多置換されている、アリールあるいはヘテロアリールを表し、
R7は、(C=O)−R、(C=O)−NR2、(C=O)−OR、HまたはAを表し、ここで、R5およびR7は、一緒になって−(CH2)n−を表わしていてもよく、
mは、0、1または2を表し、
nは、0、1、2、3、4、5、6または7を表し、
pは、0、1、2、3、4、または5を表し、好ましくは2または3を表し、
Sは、0、1、2、3、4、5、6または7を表し、好ましくは0を表す)
ならびにそれらの薬学的に利用可能な誘導体、溶媒和物、互変異性体、塩および立体異性体、ならびにそれらのあらゆる割合の混合物。 - R1がA、CF3、OCF3、SA、SCN、CH2CN、−OCOA、Hal、SCF3、t−ブチル、−CH(CH3)CH2CH3、イソプロピル、エチルまたはメチルを表す、請求項1に記載の化合物。
- R2がHを表す、請求項1または2に記載の化合物。
- R3がHを表す、請求項1から3の1項または複数項に記載の化合物。
- WがCHを表す、請求項1から4の1項または複数項に記載の化合物。
- R5が−(CH2)n−E−R1、−(CH2)nX(CH2)n−E−R1、−(CY2)n−E−(CY2)n−XR1、−(CY2)n−E−R1、(CH2)nCH(OH)−E−R1(式中、X、R1、E、Y、nおよびRaは、上述の意味を有する)を表わす、請求項1から5の1項または複数項に記載の化合物。
- R5が以下の意味:
(CH2)2OH、(CH2)3OH、(CH2)2NRR1、(CH2)3NRR1、(CH2)2CH(OH)CH2OH、(CH2)2CH(OH)CH2NRR1、(CH2)2CH(OH)CH2NR(CH2)2NRR1、(CH2)2CH(OH)CH2NR5(CH2)2NR、(CH2)2CH(OH)CH2−E−R1、Q、(CH2)2CH(OH)CH2NR(CH2)2OR、
(式中、R、R1、EおよびQは上述の意味を有する)
の1つを表す、請求項1から6の1項または複数項に記載の化合物。 - R6が、それぞれ非置換であるか、またはHal、CN、NO2、OH、CF3、OCH(CF3)2、OCOCH3もしくはAでモノまたはポリ置換されている、フェニル、2−、3−もしくは4−ピリジル、ピリミジル、フリルまたはチエニルを表す、請求項1から7の1項または複数項に記載の化合物。
- R6が以下の基:
の1つを表す、請求項1から8の1項または複数項に記載の化合物。 - R7がHを表す、請求項1から9の1項または複数項に記載の化合物。
- 下位式IAからIBの化合物:
(式中、R1、R5およびR6は請求項1で記載した意味を有する)
ならびにそのラセミ体または鏡像異性体の他の混合物。 - 下位式I1からI27の化合物。
- SがOを表す式Iの化合物。
- 請求項1から13に記載の式Iの化合物ならびにそれらの薬学的に利用可能な誘導体、塩、溶媒和物、互変異性体および立体異性体の調製方法であって、式IIの化合物
(式中、R1、R2およびR3は、請求項1で記載した意味を有する)
を、式IIIの化合物
(R6は、請求項1で記載した意味を有する)
および式IVの化合物
(式中、S’は0、1または2を表す)
または対応する置換化合物と反応させ、得られたテトラヒドロキノリンを酸を用いて対応するキノリンに変換し、次いで、これらを式Iの化合物に還元し、場合によっては、慣用法により基R5をさらなる基R5に変換し、
所望であれば、Hを表す基R7を、H以外の意味を有する基R7に変換し、
かつ/または、所望であれば、式Iの塩基もしくは酸をその塩の1つに変換することを特徴とする方法。 - 前記反応がプロトン酸またはルイス酸の存在下で実施されることを特徴とする、請求項14に記載の方法。
- 前記反応がトリフルオロ酢酸、ヘキサフルオロイソプロパノール、塩化ビスマス(III)、イッテルビウム(III)トリフレート、スカンジウム(III)トリフレートまたは硝酸アンモニウムセリウム(IV)の存在下で実施されることを特徴とする、請求項14または15に記載の方法。
- 請求項1から13に記載の少なくとも1種の式Iの化合物ならびに/またはそれらの薬学的に利用可能な誘導体、塩、溶媒和物、互変異性体、立体異性体およびそれらのあらゆる割合の混合物を含み、場合により賦形剤および/またはアジュバントを含む薬剤。
- 1種または複数の式Iの化合物と、ある量の1種または複数の式Vの化合物、それらの類似体および/またはそれらの代謝産物とを含む混合物。
(式中、Y'およびZ'は、それぞれ相互に独立してOまたはNを表し、R9およびR10は、それぞれ相互に独立してH、OH、ハロゲン、OC1〜10−アルキル、OCF3、NO2またはNH2を表し、nは、2以上6以下の整数を表し、R8およびR11は、それぞれ相互に独立してメタ位またはパラ位にあり、下記の群:
から選択される) - 使用される式Vの化合物がペンタミジンまたはその塩である、請求項18に記載の使用。
- 有糸分裂モータータンパク質Eg5の阻害、制御および/または調節により影響され得る疾患の治療用の薬剤の調製における、請求項1から13に記載の化合物ならびにそれらの薬学的に利用可能な誘導体、塩、溶媒和物、互変異性体、立体異性体およびそれらのあらゆる割合の混合物、または請求項18に記載の混合物の使用。
- 癌疾患の治療および予防用の薬剤の調製における、請求項1から13に記載の化合物または請求項18に記載の混合物の使用。
- 前記癌疾患が扁平上皮、膀胱、胃、腎臓、頭頚部、食道、子宮頚部、甲状腺、腸、肝臓、脳、前立腺、尿生殖路、リンパ系、胃、喉頭および/または肺の腫瘍の群からの腫瘍に関連する、請求項21に記載の使用。
- 前記腫瘍が単球性白血病、肺腺癌、小細胞肺癌、膵臓癌、神経膠芽腫、乳癌および結腸癌の群から選択される、請求項22に記載の使用。
- 治療される前記癌疾患が血液および免疫系の腫瘍である、請求項21に記載の使用。
- 前記腫瘍が急性骨髄性白血病、慢性骨髄性白血病、急性リンパ性白血病および/または慢性リンパ性白血病の群から選択される、請求項24に記載の使用。
- 治療有効量の1種または複数の式Vの化合物
(式中、Y'およびZ'は、それぞれ相互に独立してOまたはNを表し、R9およびR10は、それぞれ相互に独立してH、OH、ハロゲン、OC1〜10−アルキル、OCF3、NO2またはNH2を表し、nは、2以上6以下の整数を表し、R8およびR11は、それぞれ相互に独立してメタ位またはパラ位にあり、下記の基:
から選択される)、
その類似体ならびに/またはその代謝産物と組み合わせた、腫瘍の治療用薬剤の調製における請求項1から13に記載の式Iの化合物ならびに/またはそれらの生理学的に許容され得る塩および溶媒和物の使用であって、
式Iの化合物と、式Vの化合物、その類似体および/またはその代謝産物とが同時にまたは相互に14日以内に、腫瘍または他の過剰増殖細胞の増殖を阻害するのに十分な量で投与される使用。 - 使用される式Vの化合物がペンタミジンまたはその塩である、請求項26に記載の使用。
- 腫瘍の治療用薬剤の調製における請求項1から13に記載の式Iの化合物ならびに/またはそれらの生理学的に許容され得る塩および溶媒和物の使用であって、治療有効量の式Iの化合物を、放射線療法と、1)エストロゲン受容体モジュレーター、2)アンドロゲン受容体モジュレーター、3)、レチノイド受容体モジュレーター、4)細胞毒性薬、5)抗増殖剤、6)プレニルタンパク質トランスフェラーゼ阻害剤、7)HMG−CoAレダクターゼ阻害剤、8)HIVプロテアーゼ阻害剤、9)逆転写酵素阻害剤および10)さらなる血管新生阻害剤の群からの化合物と組み合わせて投与する使用。
- 式1Aの化合物。
(式中、R1、R2、R3、R5およびR6は上述の意味を有する) - 式Iの化合物の調製における式1Aの化合物の請求項28に記載の使用。
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TW200934785A (en) | 2007-10-19 | 2009-08-16 | Schering Corp | Compounds for inhibiting KSP kinesin activity |
JP2013075830A (ja) * | 2010-02-03 | 2013-04-25 | Taisho Pharmaceutical Co Ltd | キノリン誘導体 |
US9498540B2 (en) | 2013-03-15 | 2016-11-22 | Novartis Ag | Cell proliferation inhibitors and conjugates thereof |
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SI1891011T1 (sl) | 2011-04-29 |
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