US20070219197A1 - Pyridyl alkene and pyridyl alkine- acid amides as cytostatics and immuno-suppressives - Google Patents
Pyridyl alkene and pyridyl alkine- acid amides as cytostatics and immuno-suppressives Download PDFInfo
- Publication number
- US20070219197A1 US20070219197A1 US11/635,157 US63515706A US2007219197A1 US 20070219197 A1 US20070219197 A1 US 20070219197A1 US 63515706 A US63515706 A US 63515706A US 2007219197 A1 US2007219197 A1 US 2007219197A1
- Authority
- US
- United States
- Prior art keywords
- alkyl
- hydrogen
- ring
- hydroxy
- group
- 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.)
- Abandoned
Links
- 239000000824 cytostatic agent Substances 0.000 title claims abstract description 18
- 229940125721 immunosuppressive agent Drugs 0.000 title claims abstract description 7
- -1 Pyridyl alkene Chemical class 0.000 title claims description 502
- 125000004076 pyridyl group Chemical group 0.000 title claims description 25
- 230000001506 immunosuppresive effect Effects 0.000 title claims description 11
- 230000001085 cytostatic effect Effects 0.000 title claims description 8
- 150000001875 compounds Chemical class 0.000 claims abstract description 165
- 239000003814 drug Substances 0.000 claims abstract description 46
- 238000000034 method Methods 0.000 claims abstract description 37
- 238000004519 manufacturing process Methods 0.000 claims abstract description 33
- 239000003018 immunosuppressive agent Substances 0.000 claims abstract description 6
- 239000001257 hydrogen Substances 0.000 claims description 167
- 229910052739 hydrogen Inorganic materials 0.000 claims description 167
- 125000003118 aryl group Chemical group 0.000 claims description 108
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 100
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 94
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 84
- 239000000203 mixture Substances 0.000 claims description 83
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 82
- 239000004480 active ingredient Substances 0.000 claims description 75
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 75
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims description 73
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 63
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 58
- 239000000243 solution Substances 0.000 claims description 58
- 239000002904 solvent Substances 0.000 claims description 57
- 238000006243 chemical reaction Methods 0.000 claims description 55
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 54
- 229910052757 nitrogen Inorganic materials 0.000 claims description 53
- 239000000126 substance Substances 0.000 claims description 51
- 125000000623 heterocyclic group Chemical group 0.000 claims description 49
- 125000006413 ring segment Chemical group 0.000 claims description 49
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 47
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 45
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 45
- 239000011737 fluorine Substances 0.000 claims description 45
- 229910052731 fluorine Inorganic materials 0.000 claims description 45
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 44
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 42
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 42
- 229910052736 halogen Inorganic materials 0.000 claims description 42
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 40
- 150000002367 halogens Chemical class 0.000 claims description 40
- 125000001424 substituent group Chemical group 0.000 claims description 40
- 125000000217 alkyl group Chemical group 0.000 claims description 39
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 38
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 37
- 125000005842 heteroatom Chemical group 0.000 claims description 36
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 36
- 150000003839 salts Chemical class 0.000 claims description 36
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 34
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 34
- 239000002253 acid Substances 0.000 claims description 34
- 239000003795 chemical substances by application Substances 0.000 claims description 33
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 32
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 32
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 31
- 239000002585 base Substances 0.000 claims description 30
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 29
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 29
- 125000004432 carbon atom Chemical group C* 0.000 claims description 29
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 27
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 27
- 229920006395 saturated elastomer Polymers 0.000 claims description 26
- 239000000843 powder Substances 0.000 claims description 24
- 239000002671 adjuvant Substances 0.000 claims description 23
- 125000004122 cyclic group Chemical group 0.000 claims description 23
- 239000000443 aerosol Substances 0.000 claims description 21
- SFJGCXYXEFWEBK-UHFFFAOYSA-N oxazepine Chemical compound O1C=CC=CC=N1 SFJGCXYXEFWEBK-UHFFFAOYSA-N 0.000 claims description 21
- 239000003826 tablet Substances 0.000 claims description 21
- 125000003545 alkoxy group Chemical group 0.000 claims description 20
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 20
- 125000001153 fluoro group Chemical group F* 0.000 claims description 20
- 238000009472 formulation Methods 0.000 claims description 20
- 125000001624 naphthyl group Chemical group 0.000 claims description 20
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 19
- XYOVOXDWRFGKEX-UHFFFAOYSA-N azepine Chemical compound N1C=CC=CC=C1 XYOVOXDWRFGKEX-UHFFFAOYSA-N 0.000 claims description 19
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 19
- NYERMPLPURRVGM-UHFFFAOYSA-N thiazepine Chemical compound S1C=CC=CC=N1 NYERMPLPURRVGM-UHFFFAOYSA-N 0.000 claims description 19
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims description 18
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 18
- 239000000725 suspension Substances 0.000 claims description 18
- 125000006193 alkinyl group Chemical group 0.000 claims description 17
- 125000003342 alkenyl group Chemical group 0.000 claims description 16
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 claims description 16
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 15
- 125000004070 6 membered heterocyclic group Chemical group 0.000 claims description 14
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 14
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 14
- 125000004618 benzofuryl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 14
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 claims description 14
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 14
- 230000001225 therapeutic effect Effects 0.000 claims description 14
- 125000006828 (C2-C7) alkoxycarbonyl group Chemical group 0.000 claims description 13
- 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 claims description 13
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 claims description 13
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 13
- 125000003016 chromanyl group Chemical group O1C(CCC2=CC=CC=C12)* 0.000 claims description 13
- 125000001041 indolyl group Chemical group 0.000 claims description 13
- 239000008101 lactose Substances 0.000 claims description 13
- 229910052760 oxygen Inorganic materials 0.000 claims description 13
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Chemical group O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims description 13
- 239000003380 propellant Substances 0.000 claims description 13
- 125000005493 quinolyl group Chemical group 0.000 claims description 13
- 125000001544 thienyl group Chemical group 0.000 claims description 13
- 125000006832 (C1-C10) alkylene group Chemical group 0.000 claims description 12
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 claims description 12
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 12
- ZSIQJIWKELUFRJ-UHFFFAOYSA-N azepane Chemical compound C1CCCNCC1 ZSIQJIWKELUFRJ-UHFFFAOYSA-N 0.000 claims description 12
- 125000002541 furyl group Chemical group 0.000 claims description 12
- 125000004043 oxo group Chemical group O=* 0.000 claims description 12
- 239000007787 solid Substances 0.000 claims description 12
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 12
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 11
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 claims description 11
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 11
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 claims description 11
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 11
- 150000001735 carboxylic acids Chemical class 0.000 claims description 11
- 125000002883 imidazolyl group Chemical group 0.000 claims description 11
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 11
- 125000001715 oxadiazolyl group Chemical group 0.000 claims description 11
- 125000002971 oxazolyl group Chemical group 0.000 claims description 11
- 238000002360 preparation method Methods 0.000 claims description 11
- 238000000746 purification Methods 0.000 claims description 11
- 229910052717 sulfur Inorganic materials 0.000 claims description 11
- 125000001113 thiadiazolyl group Chemical group 0.000 claims description 11
- YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Natural products C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 claims description 10
- 125000006577 C1-C6 hydroxyalkyl group Chemical group 0.000 claims description 10
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 10
- 125000004450 alkenylene group Chemical group 0.000 claims description 10
- 230000015572 biosynthetic process Effects 0.000 claims description 10
- 239000000969 carrier Substances 0.000 claims description 10
- 150000002148 esters Chemical class 0.000 claims description 10
- 125000003454 indenyl group Chemical group C1(C=CC2=CC=CC=C12)* 0.000 claims description 10
- 239000012442 inert solvent Substances 0.000 claims description 10
- 238000002347 injection Methods 0.000 claims description 10
- 239000007924 injection Substances 0.000 claims description 10
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 10
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 10
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 10
- 238000002560 therapeutic procedure Methods 0.000 claims description 10
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 9
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 9
- 125000002947 alkylene group Chemical group 0.000 claims description 9
- 239000000839 emulsion Substances 0.000 claims description 9
- 150000002170 ethers Chemical class 0.000 claims description 9
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 claims description 9
- 230000002496 gastric effect Effects 0.000 claims description 9
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 9
- 125000000335 thiazolyl group Chemical group 0.000 claims description 9
- 125000006823 (C1-C6) acyl group Chemical group 0.000 claims description 8
- UKHJNJFJCGBKSF-UHFFFAOYSA-N 2,5-diazabicyclo[2.2.1]heptane Chemical compound C1NC2CNC1C2 UKHJNJFJCGBKSF-UHFFFAOYSA-N 0.000 claims description 8
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 8
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 8
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims description 8
- 125000000641 acridinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3C=C12)* 0.000 claims description 8
- 125000002252 acyl group Chemical group 0.000 claims description 8
- 125000004419 alkynylene group Chemical group 0.000 claims description 8
- 150000001408 amides Chemical class 0.000 claims description 8
- 125000003277 amino group Chemical group 0.000 claims description 8
- 125000005428 anthryl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C3C(*)=C([H])C([H])=C([H])C3=C([H])C2=C1[H] 0.000 claims description 8
- 125000004601 benzofurazanyl group Chemical group N1=C2C(=NO1)C(=CC=C2)* 0.000 claims description 8
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 8
- 229910052794 bromium Inorganic materials 0.000 claims description 8
- 239000000460 chlorine Substances 0.000 claims description 8
- 229910052801 chlorine Inorganic materials 0.000 claims description 8
- 125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 claims description 8
- 239000012530 fluid Substances 0.000 claims description 8
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 claims description 8
- GWVMLCQWXVFZCN-UHFFFAOYSA-N isoindoline Chemical compound C1=CC=C2CNCC2=C1 GWVMLCQWXVFZCN-UHFFFAOYSA-N 0.000 claims description 8
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 8
- 125000002950 monocyclic group Chemical group 0.000 claims description 8
- 239000002674 ointment Substances 0.000 claims description 8
- 125000001484 phenothiazinyl group Chemical group C1(=CC=CC=2SC3=CC=CC=C3NC12)* 0.000 claims description 8
- 125000002098 pyridazinyl group Chemical group 0.000 claims description 8
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 claims description 8
- LBUJPTNKIBCYBY-UHFFFAOYSA-N tetrahydroquinoline Natural products C1=CC=C2CCCNC2=C1 LBUJPTNKIBCYBY-UHFFFAOYSA-N 0.000 claims description 8
- RZEKHHBDFHVIKG-HRNDJLQDSA-N (e)-n-[2-(1-benzylpiperidin-4-yl)ethyl]-3-pyridin-3-ylprop-2-enamide;hydrochloride Chemical compound Cl.C=1C=CN=CC=1/C=C/C(=O)NCCC(CC1)CCN1CC1=CC=CC=C1 RZEKHHBDFHVIKG-HRNDJLQDSA-N 0.000 claims description 7
- LVGUZGTVOIAKKC-UHFFFAOYSA-N 1,1,1,2-tetrafluoroethane Chemical compound FCC(F)(F)F LVGUZGTVOIAKKC-UHFFFAOYSA-N 0.000 claims description 7
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 7
- CVEXTAUZJWYDJX-UHFFFAOYSA-N 1,3,4,10-Tetrahydro-9(2H)-acridinone Chemical compound N1C2=CC=CC=C2C(=O)C2=C1CCCC2 CVEXTAUZJWYDJX-UHFFFAOYSA-N 0.000 claims description 7
- 241001465754 Metazoa Species 0.000 claims description 7
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 7
- 150000007513 acids Chemical class 0.000 claims description 7
- 150000001412 amines Chemical class 0.000 claims description 7
- 125000004619 benzopyranyl group Chemical group O1C(C=CC2=C1C=CC=C2)* 0.000 claims description 7
- 125000003354 benzotriazolyl group Chemical group N1N=NC2=C1C=CC=C2* 0.000 claims description 7
- 238000009835 boiling Methods 0.000 claims description 7
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 claims description 7
- 125000005046 dihydronaphthyl group Chemical group 0.000 claims description 7
- 150000002430 hydrocarbons Chemical class 0.000 claims description 7
- 125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 claims description 7
- 125000005956 isoquinolyl group Chemical group 0.000 claims description 7
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 7
- 150000007522 mineralic acids Chemical class 0.000 claims description 7
- 150000007524 organic acids Chemical class 0.000 claims description 7
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 7
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 claims description 7
- 239000008096 xylene Substances 0.000 claims description 7
- 125000006274 (C1-C3)alkoxy group Chemical group 0.000 claims description 6
- 125000006795 (C2-C7) alkoxycarbonyloxy group Chemical group 0.000 claims description 6
- 125000004761 (C2-C7) alkylaminocarbonyl group Chemical group 0.000 claims description 6
- 125000004763 (C3-C13) dialkylaminocarbonyl group Chemical group 0.000 claims description 6
- ASSKVPFEZFQQNQ-UHFFFAOYSA-N 2-benzoxazolinone Chemical compound C1=CC=C2OC(O)=NC2=C1 ASSKVPFEZFQQNQ-UHFFFAOYSA-N 0.000 claims description 6
- YEDUAINPPJYDJZ-UHFFFAOYSA-N 2-hydroxybenzothiazole Chemical compound C1=CC=C2SC(O)=NC2=C1 YEDUAINPPJYDJZ-UHFFFAOYSA-N 0.000 claims description 6
- VSWICNJIUPRZIK-UHFFFAOYSA-N 2-piperideine Chemical compound C1CNC=CC1 VSWICNJIUPRZIK-UHFFFAOYSA-N 0.000 claims description 6
- GYLMCBOAXJVARF-UHFFFAOYSA-N 3-azabicyclo[2.2.1]heptane Chemical compound C1C2CCC1NC2 GYLMCBOAXJVARF-UHFFFAOYSA-N 0.000 claims description 6
- SNZSSCZJMVIOCR-UHFFFAOYSA-N 7-azabicyclo[2.2.1]heptane Chemical compound C1CC2CCC1N2 SNZSSCZJMVIOCR-UHFFFAOYSA-N 0.000 claims description 6
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 claims description 6
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 claims description 6
- ATUOYWHBWRKTHZ-UHFFFAOYSA-N Propane Chemical compound CCC ATUOYWHBWRKTHZ-UHFFFAOYSA-N 0.000 claims description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 6
- 125000004423 acyloxy group Chemical group 0.000 claims description 6
- 125000004414 alkyl thio group Chemical group 0.000 claims description 6
- 230000029936 alkylation Effects 0.000 claims description 6
- 238000005804 alkylation reaction Methods 0.000 claims description 6
- 150000008064 anhydrides Chemical class 0.000 claims description 6
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims description 6
- HONIICLYMWZJFZ-UHFFFAOYSA-N azetidine Chemical compound C1CNC1 HONIICLYMWZJFZ-UHFFFAOYSA-N 0.000 claims description 6
- QXNDZONIWRINJR-UHFFFAOYSA-N azocane Chemical compound C1CCCNCCC1 QXNDZONIWRINJR-UHFFFAOYSA-N 0.000 claims description 6
- 125000004603 benzisoxazolyl group Chemical group O1N=C(C2=C1C=CC=C2)* 0.000 claims description 6
- 125000005874 benzothiadiazolyl group Chemical group 0.000 claims description 6
- 125000004617 chromonyl group Chemical group O1C(=CC(C2=CC=CC=C12)=O)* 0.000 claims description 6
- 125000004598 dihydrobenzofuryl group Chemical group O1C(CC2=C1C=CC=C2)* 0.000 claims description 6
- 125000004582 dihydrobenzothienyl group Chemical group S1C(CC2=C1C=CC=C2)* 0.000 claims description 6
- 125000005678 ethenylene group Chemical group [H]C([*:1])=C([H])[*:2] 0.000 claims description 6
- 125000005677 ethinylene group Chemical group [*:2]C#C[*:1] 0.000 claims description 6
- 229930195733 hydrocarbon Natural products 0.000 claims description 6
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 6
- 125000001786 isothiazolyl group Chemical group 0.000 claims description 6
- 239000007788 liquid Substances 0.000 claims description 6
- 125000004593 naphthyridinyl group Chemical group N1=C(C=CC2=CC=CN=C12)* 0.000 claims description 6
- 235000005985 organic acids Nutrition 0.000 claims description 6
- AQNQGBUEVCAVML-UHFFFAOYSA-N oxazepane Chemical compound C1CCNOCC1 AQNQGBUEVCAVML-UHFFFAOYSA-N 0.000 claims description 6
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 6
- 239000003880 polar aprotic solvent Substances 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 claims description 6
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 6
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 claims description 6
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 claims description 6
- 239000007921 spray Substances 0.000 claims description 6
- 150000003459 sulfonic acid esters Chemical class 0.000 claims description 6
- 125000001425 triazolyl group Chemical group 0.000 claims description 6
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 5
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 5
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 claims description 5
- CFTOTSJVQRFXOF-UHFFFAOYSA-N 2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole Chemical compound N1C2=CC=CC=C2C2=C1CNCC2 CFTOTSJVQRFXOF-UHFFFAOYSA-N 0.000 claims description 5
- DGGKXQQCVPAUEA-UHFFFAOYSA-N 8-azabicyclo[3.2.1]octane Chemical compound C1CCC2CCC1N2 DGGKXQQCVPAUEA-UHFFFAOYSA-N 0.000 claims description 5
- 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 claims description 5
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical class Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 5
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 5
- VWBYXJRDIQCSLW-UHFFFAOYSA-N O=[P](c1ccccc1)c1ccccc1 Chemical group O=[P](c1ccccc1)c1ccccc1 VWBYXJRDIQCSLW-UHFFFAOYSA-N 0.000 claims description 5
- XSTXAVWGXDQKEL-UHFFFAOYSA-N Trichloroethylene Chemical group ClC=C(Cl)Cl XSTXAVWGXDQKEL-UHFFFAOYSA-N 0.000 claims description 5
- 125000003302 alkenyloxy group Chemical group 0.000 claims description 5
- 125000000609 carbazolyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3NC12)* 0.000 claims description 5
- 239000003085 diluting agent Substances 0.000 claims description 5
- 239000003937 drug carrier Substances 0.000 claims description 5
- 239000008103 glucose Substances 0.000 claims description 5
- 238000001802 infusion Methods 0.000 claims description 5
- 125000003386 piperidinyl group Chemical group 0.000 claims description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 5
- 230000009257 reactivity Effects 0.000 claims description 5
- 230000002459 sustained effect Effects 0.000 claims description 5
- 125000004306 triazinyl group Chemical group 0.000 claims description 5
- UBOXGVDOUJQMTN-UHFFFAOYSA-N trichloroethylene Natural products ClCC(Cl)Cl UBOXGVDOUJQMTN-UHFFFAOYSA-N 0.000 claims description 5
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 4
- 125000004739 (C1-C6) alkylsulfonyl group Chemical group 0.000 claims description 4
- QLDQYRDCPNBPII-UHFFFAOYSA-N 1,2-benzoxazol-3-one Chemical compound C1=CC=C2C(O)=NOC2=C1 QLDQYRDCPNBPII-UHFFFAOYSA-N 0.000 claims description 4
- NDOVLWQBFFJETK-UHFFFAOYSA-N 1,4-thiazinane 1,1-dioxide Chemical compound O=S1(=O)CCNCC1 NDOVLWQBFFJETK-UHFFFAOYSA-N 0.000 claims description 4
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 claims description 4
- WJFKNYWRSNBZNX-UHFFFAOYSA-N 10H-phenothiazine Chemical compound C1=CC=C2NC3=CC=CC=C3SC2=C1 WJFKNYWRSNBZNX-UHFFFAOYSA-N 0.000 claims description 4
- TZMSYXZUNZXBOL-UHFFFAOYSA-N 10H-phenoxazine Chemical compound C1=CC=C2NC3=CC=CC=C3OC2=C1 TZMSYXZUNZXBOL-UHFFFAOYSA-N 0.000 claims description 4
- XHYAKZQOCMEICX-UHFFFAOYSA-N 1h-[1,3]oxazolo[5,4-b]pyridin-2-one Chemical compound C1=CN=C2OC(=O)NC2=C1 XHYAKZQOCMEICX-UHFFFAOYSA-N 0.000 claims description 4
- DJWDAKFSDBOQJK-UHFFFAOYSA-N 2,5-diazabicyclo[2.2.2]octane Chemical compound C1NC2CCC1NC2 DJWDAKFSDBOQJK-UHFFFAOYSA-N 0.000 claims description 4
- CFMZSMGAMPBRBE-UHFFFAOYSA-N 2-hydroxyisoindole-1,3-dione Chemical compound C1=CC=C2C(=O)N(O)C(=O)C2=C1 CFMZSMGAMPBRBE-UHFFFAOYSA-N 0.000 claims description 4
- KPUSZZFAYGWAHZ-UHFFFAOYSA-N 3-azabicyclo[2.2.2]octane Chemical compound C1CC2CCC1NC2 KPUSZZFAYGWAHZ-UHFFFAOYSA-N 0.000 claims description 4
- VIQDTRXYTKXIMM-UHFFFAOYSA-N 5h-benzo[d][1]benzazepine Chemical compound N1C=CC2=CC=CC=C2C2=CC=CC=C12 VIQDTRXYTKXIMM-UHFFFAOYSA-N 0.000 claims description 4
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 4
- ATPGYYPVVKZFGR-UHFFFAOYSA-N 9-azabicyclo[3.3.1]nonane Chemical compound C1CCC2CCCC1N2 ATPGYYPVVKZFGR-UHFFFAOYSA-N 0.000 claims description 4
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims description 4
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 claims description 4
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 4
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 4
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 4
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 claims description 4
- 229910019142 PO4 Inorganic materials 0.000 claims description 4
- 125000005108 alkenylthio group Chemical group 0.000 claims description 4
- 125000004457 alkyl amino carbonyl group Chemical group 0.000 claims description 4
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 4
- 230000003327 cancerostatic effect Effects 0.000 claims description 4
- 239000002775 capsule Substances 0.000 claims description 4
- 150000008280 chlorinated hydrocarbons Chemical class 0.000 claims description 4
- 150000001805 chlorine compounds Chemical class 0.000 claims description 4
- 239000012141 concentrate Substances 0.000 claims description 4
- 238000009833 condensation Methods 0.000 claims description 4
- 230000005494 condensation Effects 0.000 claims description 4
- 125000000000 cycloalkoxy group Chemical group 0.000 claims description 4
- 125000004663 dialkyl amino group Chemical group 0.000 claims description 4
- 125000004473 dialkylaminocarbonyl group Chemical group 0.000 claims description 4
- QPMLSUSACCOBDK-UHFFFAOYSA-N diazepane Chemical compound C1CCNNCC1 QPMLSUSACCOBDK-UHFFFAOYSA-N 0.000 claims description 4
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 claims description 4
- 125000005843 halogen group Chemical group 0.000 claims description 4
- 150000003840 hydrochlorides Chemical class 0.000 claims description 4
- 125000005945 imidazopyridyl group Chemical group 0.000 claims description 4
- 239000007943 implant Substances 0.000 claims description 4
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 claims description 4
- 239000013067 intermediate product Substances 0.000 claims description 4
- 239000011630 iodine Substances 0.000 claims description 4
- 229910052740 iodine Inorganic materials 0.000 claims description 4
- JXDYKVIHCLTXOP-UHFFFAOYSA-N isatin Chemical compound C1=CC=C2C(=O)C(=O)NC2=C1 JXDYKVIHCLTXOP-UHFFFAOYSA-N 0.000 claims description 4
- 239000012948 isocyanate Substances 0.000 claims description 4
- 150000002513 isocyanates Chemical class 0.000 claims description 4
- LKPFBGKZCCBZDK-UHFFFAOYSA-N n-hydroxypiperidine Chemical compound ON1CCCCC1 LKPFBGKZCCBZDK-UHFFFAOYSA-N 0.000 claims description 4
- 125000005561 phenanthryl group Chemical group 0.000 claims description 4
- 235000021317 phosphate Nutrition 0.000 claims description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 4
- USPWKWBDZOARPV-UHFFFAOYSA-N pyrazolidine Chemical compound C1CNNC1 USPWKWBDZOARPV-UHFFFAOYSA-N 0.000 claims description 4
- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical compound OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 claims description 4
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 claims description 4
- 238000006467 substitution reaction Methods 0.000 claims description 4
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 4
- 150000003467 sulfuric acid derivatives Chemical class 0.000 claims description 4
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 claims description 4
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 claims description 4
- UXJHQQLYKUVLIE-UHFFFAOYSA-N 1,2-dihydroacridine Chemical compound C1=CC=C2N=C(C=CCC3)C3=CC2=C1 UXJHQQLYKUVLIE-UHFFFAOYSA-N 0.000 claims description 3
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims description 3
- WYVFAIDIZFAWMI-UHFFFAOYSA-N 5-azabicyclo[2.1.1]hexane Chemical compound C1CC2CC1N2 WYVFAIDIZFAWMI-UHFFFAOYSA-N 0.000 claims description 3
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 claims description 3
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 3
- KPBNHDGDUADAGP-UHFFFAOYSA-N N-[4-(1-benzoyl-4-piperidinyl)butyl]-3-(3-pyridinyl)-2-propenamide Chemical compound C=1C=CN=CC=1C=CC(=O)NCCCCC(CC1)CCN1C(=O)C1=CC=CC=C1 KPBNHDGDUADAGP-UHFFFAOYSA-N 0.000 claims description 3
- 150000001298 alcohols Chemical class 0.000 claims description 3
- 125000005194 alkoxycarbonyloxy group Chemical group 0.000 claims description 3
- 125000002529 biphenylenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3C12)* 0.000 claims description 3
- 239000001273 butane Substances 0.000 claims description 3
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 3
- AOGYCOYQMAVAFD-UHFFFAOYSA-N chlorocarbonic acid Chemical class OC(Cl)=O AOGYCOYQMAVAFD-UHFFFAOYSA-N 0.000 claims description 3
- 150000001860 citric acid derivatives Chemical class 0.000 claims description 3
- 238000010790 dilution Methods 0.000 claims description 3
- 239000012895 dilution Substances 0.000 claims description 3
- UKACHOXRXFQJFN-UHFFFAOYSA-N heptafluoropropane Chemical compound FC(F)C(F)(F)C(F)(F)F UKACHOXRXFQJFN-UHFFFAOYSA-N 0.000 claims description 3
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 claims description 3
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical class I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims description 3
- 150000002576 ketones Chemical class 0.000 claims description 3
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 3
- VSVRCYXABIWTGN-UHFFFAOYSA-N n-[3-(1-benzylpiperidin-4-yl)oxypropyl]-3-pyridin-3-ylprop-2-enamide Chemical compound C=1C=CN=CC=1C=CC(=O)NCCCOC(CC1)CCN1CC1=CC=CC=C1 VSVRCYXABIWTGN-UHFFFAOYSA-N 0.000 claims description 3
- UKIJHEJCBUYBPK-UHFFFAOYSA-N n-[4-(1-diphenylphosphorylpiperidin-4-yl)butyl]-3-pyridin-3-ylprop-2-enamide Chemical compound C=1C=CN=CC=1C=CC(=O)NCCCCC(CC1)CCN1P(=O)(C=1C=CC=CC=1)C1=CC=CC=C1 UKIJHEJCBUYBPK-UHFFFAOYSA-N 0.000 claims description 3
- ZJLVRSLKSLHYMZ-UHFFFAOYSA-N n-[4-(1-naphthalen-2-ylsulfonylpiperidin-4-yl)butyl]-3-pyridin-3-ylprop-2-enamide Chemical compound C1CN(S(=O)(=O)C=2C=C3C=CC=CC3=CC=2)CCC1CCCCNC(=O)C=CC1=CC=CN=C1 ZJLVRSLKSLHYMZ-UHFFFAOYSA-N 0.000 claims description 3
- PQJHAVGHPXLTQD-UHFFFAOYSA-N n-[4-[1-(2,2-diphenylacetyl)piperidin-4-yl]butyl]-3-pyridin-3-ylprop-2-enamide Chemical compound C=1C=CN=CC=1C=CC(=O)NCCCCC(CC1)CCN1C(=O)C(C=1C=CC=CC=1)C1=CC=CC=C1 PQJHAVGHPXLTQD-UHFFFAOYSA-N 0.000 claims description 3
- OSTHEGPTOJALEX-UHFFFAOYSA-N n-[4-[1-(6,11-dihydrobenzo[c][1]benzothiepin-11-yl)piperidin-4-yl]butyl]-3-pyridin-3-ylprop-2-enamide Chemical compound C1CN(C2C3=CC=CC=C3SCC3=CC=CC=C32)CCC1CCCCNC(=O)C=CC1=CC=CN=C1 OSTHEGPTOJALEX-UHFFFAOYSA-N 0.000 claims description 3
- IJDNQMDRQITEOD-UHFFFAOYSA-N n-butane Chemical compound CCCC IJDNQMDRQITEOD-UHFFFAOYSA-N 0.000 claims description 3
- 125000004193 piperazinyl group Chemical group 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- 235000011181 potassium carbonates Nutrition 0.000 claims description 3
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 3
- 239000001294 propane Substances 0.000 claims description 3
- 230000009885 systemic effect Effects 0.000 claims description 3
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 claims description 3
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 claims description 3
- KANAPVJGZDNSCZ-UHFFFAOYSA-N 1,2-benzothiazole 1-oxide Chemical compound C1=CC=C2S(=O)N=CC2=C1 KANAPVJGZDNSCZ-UHFFFAOYSA-N 0.000 claims description 2
- SWEICGMKXPNXNU-UHFFFAOYSA-N 1,2-dihydroindazol-3-one Chemical compound C1=CC=C2C(O)=NNC2=C1 SWEICGMKXPNXNU-UHFFFAOYSA-N 0.000 claims description 2
- XBVTWEMNKKHPEH-UHFFFAOYSA-N 1,2-dihydropyrazolo[4,3-b]pyridin-3-one Chemical class C1=CN=C2C(=O)NNC2=C1 XBVTWEMNKKHPEH-UHFFFAOYSA-N 0.000 claims description 2
- SILNNFMWIMZVEQ-UHFFFAOYSA-N 1,3-dihydrobenzimidazol-2-one Chemical compound C1=CC=C2NC(O)=NC2=C1 SILNNFMWIMZVEQ-UHFFFAOYSA-N 0.000 claims description 2
- PGDIPOWQYRAOSK-UHFFFAOYSA-N 1,3-dihydroimidazo[4,5-b]pyridin-2-one Chemical class C1=CN=C2NC(=O)NC2=C1 PGDIPOWQYRAOSK-UHFFFAOYSA-N 0.000 claims description 2
- ZNGWEEUXTBNKFR-UHFFFAOYSA-N 1,4-oxazepane Chemical group C1CNCCOC1 ZNGWEEUXTBNKFR-UHFFFAOYSA-N 0.000 claims description 2
- XHLHPRDBBAGVEG-UHFFFAOYSA-N 1-tetralone Chemical compound C1=CC=C2C(=O)CCCC2=C1 XHLHPRDBBAGVEG-UHFFFAOYSA-N 0.000 claims description 2
- NDVAMUMVOJRAJV-UHFFFAOYSA-N 10h-phenanthren-9-one Chemical compound C1=CC=C2C(=O)CC3=CC=CC=C3C2=C1 NDVAMUMVOJRAJV-UHFFFAOYSA-N 0.000 claims description 2
- HXNDHWLIFLZUKR-UHFFFAOYSA-N 1h-[1,3]thiazolo[5,4-b]pyridin-2-one Chemical class C1=CN=C2SC(O)=NC2=C1 HXNDHWLIFLZUKR-UHFFFAOYSA-N 0.000 claims description 2
- 125000004793 2,2,2-trifluoroethoxy group Chemical group FC(CO*)(F)F 0.000 claims description 2
- 125000006067 2,2-dimethyl-3-butenyl group Chemical group 0.000 claims description 2
- YQTCQNIPQMJNTI-UHFFFAOYSA-N 2,2-dimethylpropan-1-one Chemical group CC(C)(C)[C]=O YQTCQNIPQMJNTI-UHFFFAOYSA-N 0.000 claims description 2
- ZBFZXENHYIJZGA-UHFFFAOYSA-N 2,3,4,4a-tetrahydrocarbazol-1-one Chemical compound C1=CC=C2C3CCCC(=O)C3=NC2=C1 ZBFZXENHYIJZGA-UHFFFAOYSA-N 0.000 claims description 2
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 claims description 2
- 125000006040 2-hexenyl group Chemical group 0.000 claims description 2
- 125000006029 2-methyl-2-butenyl group Chemical group 0.000 claims description 2
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 2
- WYJIOQHUAOQNAZ-UHFFFAOYSA-N 2h-cyclohepta[e][1]benzothiole 3-oxide Chemical class C1=CC=CC=C2C3=CCS(=O)C3=CC=C21 WYJIOQHUAOQNAZ-UHFFFAOYSA-N 0.000 claims description 2
- TZOYXRMEFDYWDQ-UHFFFAOYSA-N 3,4-dihydro-1h-quinolin-2-one Chemical compound C1=CC=C2NC(=O)CCC2=C1 TZOYXRMEFDYWDQ-UHFFFAOYSA-N 0.000 claims description 2
- FTAHXMZRJCZXDL-UHFFFAOYSA-N 3-piperideine Chemical group C1CC=CCN1 FTAHXMZRJCZXDL-UHFFFAOYSA-N 0.000 claims description 2
- MSTDXOZUKAQDRL-UHFFFAOYSA-N 4-Chromanone Chemical compound C1=CC=C2C(=O)CCOC2=C1 MSTDXOZUKAQDRL-UHFFFAOYSA-N 0.000 claims description 2
- XRHGYUZYPHTUJZ-UHFFFAOYSA-M 4-chlorobenzoate Chemical compound [O-]C(=O)C1=CC=C(Cl)C=C1 XRHGYUZYPHTUJZ-UHFFFAOYSA-M 0.000 claims description 2
- FJKROLUGYXJWQN-UHFFFAOYSA-M 4-hydroxybenzoate Chemical compound OC1=CC=C(C([O-])=O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-M 0.000 claims description 2
- ZEYHEAKUIGZSGI-UHFFFAOYSA-N 4-methoxybenzoic acid Chemical compound COC1=CC=C(C(O)=O)C=C1 ZEYHEAKUIGZSGI-UHFFFAOYSA-N 0.000 claims description 2
- 125000003119 4-methyl-3-pentenyl group Chemical group [H]\C(=C(/C([H])([H])[H])C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000006043 5-hexenyl group Chemical group 0.000 claims description 2
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims description 2
- GDALETGZDYOOGB-UHFFFAOYSA-N Acridone Natural products C1=C(O)C=C2N(C)C3=CC=CC=C3C(=O)C2=C1O GDALETGZDYOOGB-UHFFFAOYSA-N 0.000 claims description 2
- 125000002853 C1-C4 hydroxyalkyl group Chemical group 0.000 claims description 2
- 239000004215 Carbon black (E152) Substances 0.000 claims description 2
- OCUCCJIRFHNWBP-IYEMJOQQSA-L Copper gluconate Chemical class [Cu+2].OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O.OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O OCUCCJIRFHNWBP-IYEMJOQQSA-L 0.000 claims description 2
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims description 2
- GKQLYSROISKDLL-UHFFFAOYSA-N EEDQ Chemical compound C1=CC=C2N(C(=O)OCC)C(OCC)C=CC2=C1 GKQLYSROISKDLL-UHFFFAOYSA-N 0.000 claims description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 claims description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 2
- 150000001242 acetic acid derivatives Chemical class 0.000 claims description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 2
- FZEYVTFCMJSGMP-UHFFFAOYSA-N acridone Chemical compound C1=CC=C2C(=O)C3=CC=CC=C3NC2=C1 FZEYVTFCMJSGMP-UHFFFAOYSA-N 0.000 claims description 2
- 150000001266 acyl halides Chemical group 0.000 claims description 2
- 125000001931 aliphatic group Chemical group 0.000 claims description 2
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 claims description 2
- 229910052783 alkali metal Inorganic materials 0.000 claims description 2
- 229910000288 alkali metal carbonate Inorganic materials 0.000 claims description 2
- 150000008041 alkali metal carbonates Chemical class 0.000 claims description 2
- 229910001516 alkali metal iodide Inorganic materials 0.000 claims description 2
- 125000005907 alkyl ester group Chemical group 0.000 claims description 2
- PYKYMHQGRFAEBM-UHFFFAOYSA-N anthraquinone Natural products CCC(=O)c1c(O)c2C(=O)C3C(C=CC=C3O)C(=O)c2cc1CC(=O)OC PYKYMHQGRFAEBM-UHFFFAOYSA-N 0.000 claims description 2
- 150000004056 anthraquinones Chemical class 0.000 claims description 2
- RJGDLRCDCYRQOQ-UHFFFAOYSA-N anthrone Chemical compound C1=CC=C2C(=O)C3=CC=CC=C3CC2=C1 RJGDLRCDCYRQOQ-UHFFFAOYSA-N 0.000 claims description 2
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 2
- 238000006254 arylation reaction Methods 0.000 claims description 2
- 229940072107 ascorbate Drugs 0.000 claims description 2
- 235000010323 ascorbic acid Nutrition 0.000 claims description 2
- 239000011668 ascorbic acid Substances 0.000 claims description 2
- MYONAGGJKCJOBT-UHFFFAOYSA-N benzimidazol-2-one Chemical compound C1=CC=CC2=NC(=O)N=C21 MYONAGGJKCJOBT-UHFFFAOYSA-N 0.000 claims description 2
- DMSMPAJRVJJAGA-UHFFFAOYSA-N benzo[d]isothiazol-3-one Chemical compound C1=CC=C2C(=O)NSC2=C1 DMSMPAJRVJJAGA-UHFFFAOYSA-N 0.000 claims description 2
- 150000001558 benzoic acid derivatives Chemical class 0.000 claims description 2
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 2
- HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 claims description 2
- KFDKSWDECHPONU-UHFFFAOYSA-N bis(trichloromethyl) carbonate Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl.ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl KFDKSWDECHPONU-UHFFFAOYSA-N 0.000 claims description 2
- 150000001649 bromium compounds Chemical class 0.000 claims description 2
- 150000001718 carbodiimides Chemical class 0.000 claims description 2
- 150000001244 carboxylic acid anhydrides Chemical class 0.000 claims description 2
- OTAFHZMPRISVEM-UHFFFAOYSA-N chromone Chemical compound C1=CC=C2C(=O)C=COC2=C1 OTAFHZMPRISVEM-UHFFFAOYSA-N 0.000 claims description 2
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 2
- SJOFOLAJSGAHRL-UHFFFAOYSA-N cyclohepta[f]quinolin-1-one Chemical class C1=CC=CC2=C3C(=O)C=CN=C3C=CC2=C1 SJOFOLAJSGAHRL-UHFFFAOYSA-N 0.000 claims description 2
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 2
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 2
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 2
- 230000001419 dependent effect Effects 0.000 claims description 2
- 238000003745 diagnosis Methods 0.000 claims description 2
- 125000004786 difluoromethoxy group Chemical group [H]C(F)(F)O* 0.000 claims description 2
- HSUGRBWQSSZJOP-RTWAWAEBSA-N diltiazem Chemical group C1=CC(OC)=CC=C1[C@H]1[C@@H](OC(C)=O)C(=O)N(CCN(C)C)C2=CC=CC=C2S1 HSUGRBWQSSZJOP-RTWAWAEBSA-N 0.000 claims description 2
- 125000005982 diphenylmethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 2
- 239000007938 effervescent tablet Substances 0.000 claims description 2
- 125000003700 epoxy group Chemical group 0.000 claims description 2
- YLQWCDOCJODRMT-UHFFFAOYSA-N fluoren-9-one Chemical compound C1=CC=C2C(=O)C3=CC=CC=C3C2=C1 YLQWCDOCJODRMT-UHFFFAOYSA-N 0.000 claims description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-L fumarate(2-) Chemical class [O-]C(=O)\C=C\C([O-])=O VZCYOOQTPOCHFL-OWOJBTEDSA-L 0.000 claims description 2
- 210000004392 genitalia Anatomy 0.000 claims description 2
- JFCQEDHGNNZCLN-UHFFFAOYSA-N glutaric acid Chemical compound OC(=O)CCCC(O)=O JFCQEDHGNNZCLN-UHFFFAOYSA-N 0.000 claims description 2
- 150000004820 halides Chemical class 0.000 claims description 2
- 150000008282 halocarbons Chemical class 0.000 claims description 2
- 125000004475 heteroaralkyl group Chemical group 0.000 claims description 2
- 125000004446 heteroarylalkyl group Chemical group 0.000 claims description 2
- 125000004634 hexahydroazepinyl group Chemical group N1(CCCCCC1)* 0.000 claims description 2
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- AQYSYJUIMQTRMV-UHFFFAOYSA-N hypofluorous acid Chemical compound FO AQYSYJUIMQTRMV-UHFFFAOYSA-N 0.000 claims description 2
- JXXWJMUPNZDILL-UHFFFAOYSA-N imidazo[4,5-b]pyridin-2-one Chemical class C1=CC=NC2=NC(=O)N=C21 JXXWJMUPNZDILL-UHFFFAOYSA-N 0.000 claims description 2
- QNXSIUBBGPHDDE-UHFFFAOYSA-N indan-1-one Chemical compound C1=CC=C2C(=O)CCC2=C1 QNXSIUBBGPHDDE-UHFFFAOYSA-N 0.000 claims description 2
- JYGFTBXVXVMTGB-UHFFFAOYSA-N indolin-2-one Chemical compound C1=CC=C2NC(=O)CC2=C1 JYGFTBXVXVMTGB-UHFFFAOYSA-N 0.000 claims description 2
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims description 2
- 125000005929 isobutyloxycarbonyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])OC(*)=O 0.000 claims description 2
- 238000002955 isolation Methods 0.000 claims description 2
- 125000005928 isopropyloxycarbonyl group Chemical group [H]C([H])([H])C([H])(OC(*)=O)C([H])([H])[H] 0.000 claims description 2
- 150000002688 maleic acid derivatives Chemical class 0.000 claims description 2
- 150000004701 malic acid derivatives Chemical class 0.000 claims description 2
- 125000005948 methanesulfonyloxy group Chemical group 0.000 claims description 2
- XMJHPCRAQCTCFT-UHFFFAOYSA-N methyl chloroformate Chemical compound COC(Cl)=O XMJHPCRAQCTCFT-UHFFFAOYSA-N 0.000 claims description 2
- 125000002757 morpholinyl group Chemical group 0.000 claims description 2
- YJWWURSTYVHABB-UHFFFAOYSA-N n,n-diphenyl-4-[4-(3-pyridin-3-ylprop-2-enoylamino)butyl]piperidine-1-carboxamide Chemical compound C=1C=CN=CC=1C=CC(=O)NCCCCC(CC1)CCN1C(=O)N(C=1C=CC=CC=1)C1=CC=CC=C1 YJWWURSTYVHABB-UHFFFAOYSA-N 0.000 claims description 2
- DPVVFPHRCQLSNL-UHFFFAOYSA-N n,n-diphenyl-4-[4-(5-pyridin-3-ylpenta-2,4-dienoylamino)butyl]piperidine-1-carboxamide Chemical compound C=1C=CN=CC=1C=CC=CC(=O)NCCCCC(CC1)CCN1C(=O)N(C=1C=CC=CC=1)C1=CC=CC=C1 DPVVFPHRCQLSNL-UHFFFAOYSA-N 0.000 claims description 2
- ZUFZDOAYAQWLCP-UHFFFAOYSA-N n-[(4-benzhydrylmorpholin-2-yl)methyl]-3-pyridin-3-ylprop-2-enamide Chemical compound C=1C=CN=CC=1C=CC(=O)NCC(OCC1)CN1C(C=1C=CC=CC=1)C1=CC=CC=C1 ZUFZDOAYAQWLCP-UHFFFAOYSA-N 0.000 claims description 2
- RIYGFDAGQVEUIR-UHFFFAOYSA-N n-[4-(1-acetylpiperidin-4-yl)butyl]-3-pyridin-3-ylprop-2-enamide Chemical compound C1CN(C(=O)C)CCC1CCCCNC(=O)C=CC1=CC=CN=C1 RIYGFDAGQVEUIR-UHFFFAOYSA-N 0.000 claims description 2
- BMAOVQOVHZRCHM-UHFFFAOYSA-N n-[4-(1-benzoylpiperidin-4-yl)butyl]-5-pyridin-3-ylpenta-2,4-dienamide Chemical compound C=1C=CN=CC=1C=CC=CC(=O)NCCCCC(CC1)CCN1C(=O)C1=CC=CC=C1 BMAOVQOVHZRCHM-UHFFFAOYSA-N 0.000 claims description 2
- RTGGVVSUNFQQGC-UHFFFAOYSA-N n-[4-[1-[phenyl(pyridin-4-yl)methyl]piperidin-4-yl]butyl]-3-pyridin-3-ylprop-2-enamide Chemical compound C=1C=CN=CC=1C=CC(=O)NCCCCC(CC1)CCN1C(C=1C=CN=CC=1)C1=CC=CC=C1 RTGGVVSUNFQQGC-UHFFFAOYSA-N 0.000 claims description 2
- RTOVZAWTXPBIEP-UHFFFAOYSA-N n-[5-(1-benzhydrylpiperidin-4-yl)pentyl]-5-pyridin-3-ylpenta-2,4-dienamide Chemical compound C=1C=CN=CC=1C=CC=CC(=O)NCCCCCC(CC1)CCN1C(C=1C=CC=CC=1)C1=CC=CC=C1 RTOVZAWTXPBIEP-UHFFFAOYSA-N 0.000 claims description 2
- AVZNELZWYQWZGG-UHFFFAOYSA-N n-[6-(1-benzhydrylpiperidin-4-yl)hexyl]-5-pyridin-3-ylpenta-2,4-dienamide Chemical compound C=1C=CN=CC=1C=CC=CC(=O)NCCCCCCC(CC1)CCN1C(C=1C=CC=CC=1)C1=CC=CC=C1 AVZNELZWYQWZGG-UHFFFAOYSA-N 0.000 claims description 2
- KYAMVWKIMUMBKN-UHFFFAOYSA-N n-[7-(1-benzhydrylpiperidin-4-yl)heptyl]-3-pyridin-3-ylprop-2-enamide Chemical compound C=1C=CN=CC=1C=CC(=O)NCCCCCCCC(CC1)CCN1C(C=1C=CC=CC=1)C1=CC=CC=C1 KYAMVWKIMUMBKN-UHFFFAOYSA-N 0.000 claims description 2
- AGGJAKIWECHSCV-UHFFFAOYSA-N n-[8-(1-benzhydrylpiperidin-4-yl)octyl]-3-pyridin-3-ylprop-2-enamide Chemical compound C=1C=CN=CC=1C=CC(=O)NCCCCCCCCC(CC1)CCN1C(C=1C=CC=CC=1)C1=CC=CC=C1 AGGJAKIWECHSCV-UHFFFAOYSA-N 0.000 claims description 2
- 125000001038 naphthoyl group Chemical group C1(=CC=CC2=CC=CC=C12)C(=O)* 0.000 claims description 2
- 125000005146 naphthylsulfonyl group Chemical group C1(=CC=CC2=CC=CC=C12)S(=O)(=O)* 0.000 claims description 2
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 claims description 2
- 150000007530 organic bases Chemical class 0.000 claims description 2
- 150000003891 oxalate salts Chemical class 0.000 claims description 2
- 238000004806 packaging method and process Methods 0.000 claims description 2
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 2
- AHWALFGBDFAJAI-UHFFFAOYSA-N phenyl carbonochloridate Chemical compound ClC(=O)OC1=CC=CC=C1 AHWALFGBDFAJAI-UHFFFAOYSA-N 0.000 claims description 2
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 claims description 2
- ACVYVLVWPXVTIT-UHFFFAOYSA-N phosphinic acid Chemical compound O[PH2]=O ACVYVLVWPXVTIT-UHFFFAOYSA-N 0.000 claims description 2
- 150000003013 phosphoric acid derivatives Chemical class 0.000 claims description 2
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 2
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 2
- 239000011736 potassium bicarbonate Substances 0.000 claims description 2
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 claims description 2
- 229910000105 potassium hydride Inorganic materials 0.000 claims description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 2
- 229940086066 potassium hydrogencarbonate Drugs 0.000 claims description 2
- 125000001844 prenyl group Chemical group [H]C([*])([H])C([H])=C(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 claims description 2
- 239000003586 protic polar solvent Substances 0.000 claims description 2
- TUPZMLLDXCWVKH-UHFFFAOYSA-N pyrazolo[4,3-b]pyridin-3-one Chemical class C1=CN=C2C(=O)N=NC2=C1 TUPZMLLDXCWVKH-UHFFFAOYSA-N 0.000 claims description 2
- WHMDPDGBKYUEMW-UHFFFAOYSA-N pyridine-2-thiol Chemical compound SC1=CC=CC=N1 WHMDPDGBKYUEMW-UHFFFAOYSA-N 0.000 claims description 2
- 125000005400 pyridylcarbonyl group Chemical group N1=C(C=CC=C1)C(=O)* 0.000 claims description 2
- 125000005344 pyridylmethyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 claims description 2
- LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2-ol Chemical compound C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 claims description 2
- 229930185107 quinolinone Natural products 0.000 claims description 2
- 229960001860 salicylate Drugs 0.000 claims description 2
- 150000003335 secondary amines Chemical class 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- 239000011734 sodium Substances 0.000 claims description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 2
- 239000012312 sodium hydride Substances 0.000 claims description 2
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 2
- 235000009518 sodium iodide Nutrition 0.000 claims description 2
- 125000005415 substituted alkoxy group Chemical group 0.000 claims description 2
- 150000003460 sulfonic acids Chemical class 0.000 claims description 2
- 150000003461 sulfonyl halides Chemical class 0.000 claims description 2
- 125000004434 sulfur atom Chemical group 0.000 claims description 2
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical class ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 claims description 2
- 239000000829 suppository Substances 0.000 claims description 2
- 125000006318 tert-butyl amino group Chemical group [H]N(*)C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- 125000001302 tertiary amino group Chemical group 0.000 claims description 2
- ZXLDQJLIBNPEFJ-UHFFFAOYSA-N tetrahydro-beta-carboline Natural products C1CNC(C)C2=C1C1=CC=C(OC)C=C1N2 ZXLDQJLIBNPEFJ-UHFFFAOYSA-N 0.000 claims description 2
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 2
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 2
- 125000005958 tetrahydrothienyl group Chemical group 0.000 claims description 2
- 125000005302 thiazolylmethyl group Chemical group [H]C1=C([H])N=C(S1)C([H])([H])* 0.000 claims description 2
- 125000005301 thienylmethyl group Chemical group [H]C1=C([H])C([H])=C(S1)C([H])([H])* 0.000 claims description 2
- 125000003396 thiol group Chemical group [H]S* 0.000 claims description 2
- KJAMZCVTJDTESW-UHFFFAOYSA-N tiracizine Chemical compound C1CC2=CC=CC=C2N(C(=O)CN(C)C)C2=CC(NC(=O)OCC)=CC=C21 KJAMZCVTJDTESW-UHFFFAOYSA-N 0.000 claims description 2
- 125000005490 tosylate group Chemical group 0.000 claims description 2
- KQTIIICEAUMSDG-UHFFFAOYSA-N tricarballylic acid Chemical compound OC(=O)CC(C(O)=O)CC(O)=O KQTIIICEAUMSDG-UHFFFAOYSA-N 0.000 claims description 2
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 2
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 claims 13
- RAHZWNYVWXNFOC-UHFFFAOYSA-N sulfur dioxide Inorganic materials O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 claims 7
- 229940093499 ethyl acetate Drugs 0.000 claims 3
- 235000019439 ethyl acetate Nutrition 0.000 claims 3
- UWYZHKAOTLEWKK-UHFFFAOYSA-N 1,2,3,4-tetrahydroisoquinoline Chemical compound C1=CC=C2CNCCC2=C1 UWYZHKAOTLEWKK-UHFFFAOYSA-N 0.000 claims 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims 2
- JYUXDXWXTPSAEL-UHFFFAOYSA-N 1,4-dioxane;oxolane Chemical compound C1CCOC1.C1COCCO1 JYUXDXWXTPSAEL-UHFFFAOYSA-N 0.000 claims 1
- NWRGSJMGYZJGDP-UHFFFAOYSA-N 2,3-dihydro-1H-benzo[d][1]benzazepine Chemical compound N1=CC=C2C=CC=CC2=C2CCCC=C21 NWRGSJMGYZJGDP-UHFFFAOYSA-N 0.000 claims 1
- BMVWCPGVLSILMU-UHFFFAOYSA-N 5,6-dihydrodibenzo[2,1-b:2',1'-f][7]annulen-11-one Chemical compound C1CC2=CC=CC=C2C(=O)C2=CC=CC=C21 BMVWCPGVLSILMU-UHFFFAOYSA-N 0.000 claims 1
- VJPPDEZWWKCSIV-UHFFFAOYSA-N 6-azabicyclo[3.2.1]octane Chemical compound C1C2CNC1CCC2 VJPPDEZWWKCSIV-UHFFFAOYSA-N 0.000 claims 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims 1
- 241000021559 Dicerandra Species 0.000 claims 1
- 235000010654 Melissa officinalis Nutrition 0.000 claims 1
- SLWZKXICYMTRGN-UHFFFAOYSA-N N-[4-(1-benzhydrylpiperidin-4-yl)butyl]-2-pyridin-3-ylpenta-2,4-dienamide Chemical compound C=1C=CN=CC=1C(=CC=C)C(=O)NCCCCC(CC1)CCN1C(C=1C=CC=CC=1)C1=CC=CC=C1 SLWZKXICYMTRGN-UHFFFAOYSA-N 0.000 claims 1
- ZLXHGQCMMVHJLB-UHFFFAOYSA-N N1=CC=CC2=CC=CC=C2C2=C1CCCC2 Chemical compound N1=CC=CC2=CC=CC=C2C2=C1CCCC2 ZLXHGQCMMVHJLB-UHFFFAOYSA-N 0.000 claims 1
- 125000003368 amide group Chemical group 0.000 claims 1
- 125000004429 atom Chemical group 0.000 claims 1
- ZETANZUWYPHWDA-UHFFFAOYSA-N azetidine;pyrrolidine Chemical compound C1CNC1.C1CCNC1 ZETANZUWYPHWDA-UHFFFAOYSA-N 0.000 claims 1
- 125000002619 bicyclic group Chemical group 0.000 claims 1
- 125000002837 carbocyclic group Chemical group 0.000 claims 1
- 229910002091 carbon monoxide Inorganic materials 0.000 claims 1
- 125000001887 cyclopentyloxy group Chemical group C1(CCCC1)O* 0.000 claims 1
- 125000004494 ethyl ester group Chemical group 0.000 claims 1
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 claims 1
- 239000000865 liniment Substances 0.000 claims 1
- 238000002156 mixing Methods 0.000 claims 1
- VOVXMGCWKNQLPL-UHFFFAOYSA-N n-[2-(1-benzhydrylpiperidin-2-yl)ethyl]-5-pyridin-3-ylpenta-2,4-dienamide Chemical compound C=1C=CN=CC=1C=CC=CC(=O)NCCC1CCCCN1C(C=1C=CC=CC=1)C1=CC=CC=C1 VOVXMGCWKNQLPL-UHFFFAOYSA-N 0.000 claims 1
- BDSDISAAJZRDQB-UHFFFAOYSA-N n-[3-(1-benzhydrylpiperidin-4-yl)oxypropyl]-3-pyridin-3-ylprop-2-enamide Chemical compound C=1C=CN=CC=1C=CC(=O)NCCCOC(CC1)CCN1C(C=1C=CC=CC=1)C1=CC=CC=C1 BDSDISAAJZRDQB-UHFFFAOYSA-N 0.000 claims 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims 1
- 239000011505 plaster Substances 0.000 claims 1
- UXAWXZDXVOYLII-UHFFFAOYSA-N tert-butyl 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate Chemical compound C1C2N(C(=O)OC(C)(C)C)CC1NC2 UXAWXZDXVOYLII-UHFFFAOYSA-N 0.000 claims 1
- 229940124597 therapeutic agent Drugs 0.000 claims 1
- OBIQBNMWIDNBAD-UHFFFAOYSA-N tricyclo[10.4.0.02,7]hexadeca-1,9,11,13,15-pentaen-3-one Chemical compound C1(CCCC2CC=CC=C3C(=C21)C=CC=C3)=O OBIQBNMWIDNBAD-UHFFFAOYSA-N 0.000 claims 1
- 206010028980 Neoplasm Diseases 0.000 abstract description 23
- 150000003222 pyridines Chemical class 0.000 abstract description 2
- 0 [1*]C.[2*]C.[3*]C.[4*]N([2H]CC)C(=O)*C1=CN(C)=CC=C1 Chemical compound [1*]C.[2*]C.[3*]C.[4*]N([2H]CC)C(=O)*C1=CN(C)=CC=C1 0.000 description 66
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 63
- 150000002431 hydrogen Chemical group 0.000 description 59
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 52
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 37
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 30
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 28
- JUMUTCOEYUQYER-UHFFFAOYSA-N CCCCC1CCN(C(C2=CC=CC=C2)C2=CC=CC=C2)CC1 Chemical compound CCCCC1CCN(C(C2=CC=CC=C2)C2=CC=CC=C2)CC1 JUMUTCOEYUQYER-UHFFFAOYSA-N 0.000 description 20
- 238000001816 cooling Methods 0.000 description 19
- 239000012074 organic phase Substances 0.000 description 19
- 239000000741 silica gel Substances 0.000 description 19
- 229910002027 silica gel Inorganic materials 0.000 description 19
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 17
- 238000002329 infrared spectrum Methods 0.000 description 16
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 16
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 15
- 238000012360 testing method Methods 0.000 description 14
- 239000013078 crystal Substances 0.000 description 13
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 12
- 230000000694 effects Effects 0.000 description 12
- 239000003921 oil Substances 0.000 description 12
- 235000019198 oils Nutrition 0.000 description 12
- 239000006185 dispersion Substances 0.000 description 11
- 230000007717 exclusion Effects 0.000 description 11
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 10
- 239000008188 pellet Substances 0.000 description 10
- 229910052938 sodium sulfate Inorganic materials 0.000 description 10
- 235000011152 sodium sulphate Nutrition 0.000 description 10
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 9
- 235000014113 dietary fatty acids Nutrition 0.000 description 9
- 239000000194 fatty acid Substances 0.000 description 9
- 229930195729 fatty acid Natural products 0.000 description 9
- ZHMPWNSNPCYITG-UHFFFAOYSA-N CCCCC1CCN(CC2=CC=CC=C2)CC1 Chemical compound CCCCC1CCN(CC2=CC=CC=C2)CC1 ZHMPWNSNPCYITG-UHFFFAOYSA-N 0.000 description 8
- LRMLWYXJORUTBG-UHFFFAOYSA-N CP(C)(C)=O Chemical compound CP(C)(C)=O LRMLWYXJORUTBG-UHFFFAOYSA-N 0.000 description 8
- 239000000499 gel Substances 0.000 description 8
- 229920000642 polymer Polymers 0.000 description 8
- 229920002472 Starch Polymers 0.000 description 7
- 239000008346 aqueous phase Substances 0.000 description 7
- 239000003925 fat Substances 0.000 description 7
- 235000019197 fats Nutrition 0.000 description 7
- 239000003381 stabilizer Substances 0.000 description 7
- 239000008107 starch Substances 0.000 description 7
- 235000019698 starch Nutrition 0.000 description 7
- PLDDTIUXJOKAGY-UHFFFAOYSA-N CCCCC1CCN(C(=O)C2=CC=CC=C2)CC1 Chemical compound CCCCC1CCN(C(=O)C2=CC=CC=C2)CC1 PLDDTIUXJOKAGY-UHFFFAOYSA-N 0.000 description 6
- IHKGPZWPUATOIW-UHFFFAOYSA-N CCCCC1CCN(C(=O)OC(C)(C)C)CC1 Chemical compound CCCCC1CCN(C(=O)OC(C)(C)C)CC1 IHKGPZWPUATOIW-UHFFFAOYSA-N 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 210000004027 cell Anatomy 0.000 description 6
- 239000007789 gas Substances 0.000 description 6
- 229920000159 gelatin Polymers 0.000 description 6
- 239000008273 gelatin Substances 0.000 description 6
- 239000007903 gelatin capsule Substances 0.000 description 6
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
- 239000008347 soybean phospholipid Substances 0.000 description 6
- 238000010626 work up procedure Methods 0.000 description 6
- VUVORVXMOLQFMO-ONEGZZNKSA-N (e)-3-pyridin-3-ylprop-2-enoic acid Chemical compound OC(=O)\C=C\C1=CC=CN=C1 VUVORVXMOLQFMO-ONEGZZNKSA-N 0.000 description 5
- NLHHRLWOUZZQLW-UHFFFAOYSA-N C=CC#N Chemical compound C=CC#N NLHHRLWOUZZQLW-UHFFFAOYSA-N 0.000 description 5
- YDIPLPUZIWLUFW-UHFFFAOYSA-N CCCCC1CCCN(C(C2=CC=CC=C2)C2=CC=CC=C2)C1 Chemical compound CCCCC1CCCN(C(C2=CC=CC=C2)C2=CC=CC=C2)C1 YDIPLPUZIWLUFW-UHFFFAOYSA-N 0.000 description 5
- ZVYFHWNVAPJSCY-UHFFFAOYSA-N CCCCC1CCN(SO(O)C2=CC3=CC=CC=C3C=C2)CC1 Chemical compound CCCCC1CCN(SO(O)C2=CC3=CC=CC=C3C=C2)CC1 ZVYFHWNVAPJSCY-UHFFFAOYSA-N 0.000 description 5
- XIQSPCJCAJVNJL-UHFFFAOYSA-N CCCCC1CCNCC1 Chemical compound CCCCC1CCNCC1 XIQSPCJCAJVNJL-UHFFFAOYSA-N 0.000 description 5
- 108010010803 Gelatin Proteins 0.000 description 5
- 229920002678 cellulose Polymers 0.000 description 5
- 239000006071 cream Substances 0.000 description 5
- 235000019322 gelatine Nutrition 0.000 description 5
- 235000011852 gelatine desserts Nutrition 0.000 description 5
- 230000036961 partial effect Effects 0.000 description 5
- 229920001223 polyethylene glycol Polymers 0.000 description 5
- 210000004881 tumor cell Anatomy 0.000 description 5
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 4
- SGQZUKMNVWCTQS-UHFFFAOYSA-N CCCCC1CCN(C(=O)C(C2=CC=CC=C2)C2=CC=CC=C2)CC1 Chemical compound CCCCC1CCN(C(=O)C(C2=CC=CC=C2)C2=CC=CC=C2)CC1 SGQZUKMNVWCTQS-UHFFFAOYSA-N 0.000 description 4
- MWOHLHOUGIZBDL-UHFFFAOYSA-N CCCCC1CCN(C(=O)N(C2=CC=CC=C2)C2=CC=CC=C2)CC1 Chemical compound CCCCC1CCN(C(=O)N(C2=CC=CC=C2)C2=CC=CC=C2)CC1 MWOHLHOUGIZBDL-UHFFFAOYSA-N 0.000 description 4
- 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 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 4
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 4
- HSHXDCVZWHOWCS-UHFFFAOYSA-N N'-hexadecylthiophene-2-carbohydrazide Chemical class CCCCCCCCCCCCCCCCNNC(=O)c1cccs1 HSHXDCVZWHOWCS-UHFFFAOYSA-N 0.000 description 4
- 229920001214 Polysorbate 60 Polymers 0.000 description 4
- 229920002125 Sokalan® Polymers 0.000 description 4
- 235000021355 Stearic acid Nutrition 0.000 description 4
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 4
- 239000000872 buffer Substances 0.000 description 4
- 235000013877 carbamide Nutrition 0.000 description 4
- 235000010980 cellulose Nutrition 0.000 description 4
- 239000001913 cellulose Substances 0.000 description 4
- 238000003818 flash chromatography Methods 0.000 description 4
- 150000004677 hydrates Chemical class 0.000 description 4
- 239000001866 hydroxypropyl methyl cellulose Chemical class 0.000 description 4
- 229920003088 hydroxypropyl methyl cellulose Chemical class 0.000 description 4
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- 235000010355 mannitol Nutrition 0.000 description 4
- 239000002609 medium Substances 0.000 description 4
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 4
- 239000008108 microcrystalline cellulose Substances 0.000 description 4
- 229940016286 microcrystalline cellulose Drugs 0.000 description 4
- OPZQARKHIZZICO-UHFFFAOYSA-N n-(4-piperidin-4-ylbutyl)-3-pyridin-3-ylprop-2-enamide;dihydrochloride Chemical compound Cl.Cl.C=1C=CN=CC=1C=CC(=O)NCCCCC1CCNCC1 OPZQARKHIZZICO-UHFFFAOYSA-N 0.000 description 4
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 4
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 4
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 4
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 4
- 239000003755 preservative agent Substances 0.000 description 4
- 239000000377 silicon dioxide Substances 0.000 description 4
- 239000000344 soap Substances 0.000 description 4
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 4
- 239000012453 solvate Substances 0.000 description 4
- 239000008117 stearic acid Substances 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 239000000454 talc Substances 0.000 description 4
- 235000012222 talc Nutrition 0.000 description 4
- 229910052623 talc Inorganic materials 0.000 description 4
- 230000004614 tumor growth Effects 0.000 description 4
- 229940099259 vaseline Drugs 0.000 description 4
- YFMFNYKEUDLDTL-UHFFFAOYSA-N 1,1,1,2,3,3,3-heptafluoropropane Chemical compound FC(F)(F)C(F)C(F)(F)F YFMFNYKEUDLDTL-UHFFFAOYSA-N 0.000 description 3
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 3
- HIQIXEFWDLTDED-UHFFFAOYSA-N 4-hydroxy-1-piperidin-4-ylpyrrolidin-2-one Chemical compound O=C1CC(O)CN1C1CCNCC1 HIQIXEFWDLTDED-UHFFFAOYSA-N 0.000 description 3
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 3
- LMXZIYYKBVOGFO-UHFFFAOYSA-N CC1CCN(C(C2=CC=CC=C2)C2=CC=CC=C2)CC1 Chemical compound CC1CCN(C(C2=CC=CC=C2)C2=CC=CC=C2)CC1 LMXZIYYKBVOGFO-UHFFFAOYSA-N 0.000 description 3
- NBCXZRVQEDJOBK-UHFFFAOYSA-N CC1CN(C(C2=CC=CC=C2)C2=CC=CC=C2)C1 Chemical compound CC1CN(C(C2=CC=CC=C2)C2=CC=CC=C2)C1 NBCXZRVQEDJOBK-UHFFFAOYSA-N 0.000 description 3
- YJRVTYUSMGLGOB-UHFFFAOYSA-N CC1CN(C(C2=CC=CC=C2)C2=CC=CC=C2)CCO1 Chemical compound CC1CN(C(C2=CC=CC=C2)C2=CC=CC=C2)CCO1 YJRVTYUSMGLGOB-UHFFFAOYSA-N 0.000 description 3
- UIVBMPBDCUZALC-UHFFFAOYSA-N CCC1CCN(C(C2=CC=CC=C2)C2=CC=CC=C2)CC1 Chemical compound CCC1CCN(C(C2=CC=CC=C2)C2=CC=CC=C2)CC1 UIVBMPBDCUZALC-UHFFFAOYSA-N 0.000 description 3
- QKHTVPOMTDBEQO-UHFFFAOYSA-N CCCCC1CCN(C(=O)C2=CC3=C(C=C2)C(=O)C2=C(C=CC=C2)C3=O)CC1 Chemical compound CCCCC1CCN(C(=O)C2=CC3=C(C=C2)C(=O)C2=C(C=CC=C2)C3=O)CC1 QKHTVPOMTDBEQO-UHFFFAOYSA-N 0.000 description 3
- BCYLESDZHLQEDD-UHFFFAOYSA-N CCCCC1CCN(C(=O)C2=CC=CC3=C2C2=C(C=CC=C2)C3=O)CC1 Chemical compound CCCCC1CCN(C(=O)C2=CC=CC3=C2C2=C(C=CC=C2)C3=O)CC1 BCYLESDZHLQEDD-UHFFFAOYSA-N 0.000 description 3
- XANWEDKBQOITCI-UHFFFAOYSA-N CCCCC1CCN(C(=O)C2=CC=CC3=CC=CC=C32)CC1 Chemical compound CCCCC1CCN(C(=O)C2=CC=CC3=CC=CC=C32)CC1 XANWEDKBQOITCI-UHFFFAOYSA-N 0.000 description 3
- BXVKHSJDSHASST-UHFFFAOYSA-N CCCCC1CCN(C(=O)CC(C2=CC=CC=C2)C2=CC=CC=C2)CC1 Chemical compound CCCCC1CCN(C(=O)CC(C2=CC=CC=C2)C2=CC=CC=C2)CC1 BXVKHSJDSHASST-UHFFFAOYSA-N 0.000 description 3
- PAHQCAGXUJNYCN-UHFFFAOYSA-N CCCCC1CCN(C(=O)NC2=CC=CC3=CC=CC=C32)CC1 Chemical compound CCCCC1CCN(C(=O)NC2=CC=CC3=CC=CC=C32)CC1 PAHQCAGXUJNYCN-UHFFFAOYSA-N 0.000 description 3
- OBOQLAMOYTYYDQ-UHFFFAOYSA-N CCCCC1CCN(C(C)=O)CC1 Chemical compound CCCCC1CCN(C(C)=O)CC1 OBOQLAMOYTYYDQ-UHFFFAOYSA-N 0.000 description 3
- IYKNZNRSMYEJSB-UHFFFAOYSA-N CCCCC1CCN(C(C2=CC=CC=C2Cl)C2=C(Cl)C=CC=C2)CC1 Chemical compound CCCCC1CCN(C(C2=CC=CC=C2Cl)C2=C(Cl)C=CC=C2)CC1 IYKNZNRSMYEJSB-UHFFFAOYSA-N 0.000 description 3
- GADNIRAACBUHCY-UHFFFAOYSA-N CCCCC1CCN(C2C3=C(C=CC=C3)COC3=C2C=CC=C3)CC1 Chemical compound CCCCC1CCN(C2C3=C(C=CC=C3)COC3=C2C=CC=C3)CC1 GADNIRAACBUHCY-UHFFFAOYSA-N 0.000 description 3
- QJQYNRRHHNRQKN-UHFFFAOYSA-N CCCCC1CCN(C2C3=C(C=CC=C3)CSC3=C2C=CC=C3)CC1 Chemical compound CCCCC1CCN(C2C3=C(C=CC=C3)CSC3=C2C=CC=C3)CC1 QJQYNRRHHNRQKN-UHFFFAOYSA-N 0.000 description 3
- IGKOKTKCZGTDJS-UHFFFAOYSA-N CCCCC1CCN(P(=O)(C2=CC=CC=C2)C2=CC=CC=C2)CC1 Chemical compound CCCCC1CCN(P(=O)(C2=CC=CC=C2)C2=CC=CC=C2)CC1 IGKOKTKCZGTDJS-UHFFFAOYSA-N 0.000 description 3
- 229920002307 Dextran Polymers 0.000 description 3
- 239000001856 Ethyl cellulose Substances 0.000 description 3
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical class CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 3
- 229920003134 Eudragit® polymer Polymers 0.000 description 3
- 206010062016 Immunosuppression Diseases 0.000 description 3
- 239000004721 Polyphenylene oxide Substances 0.000 description 3
- 230000009471 action Effects 0.000 description 3
- 239000002246 antineoplastic agent Substances 0.000 description 3
- 239000003963 antioxidant agent Substances 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 239000012298 atmosphere Substances 0.000 description 3
- 235000019445 benzyl alcohol Nutrition 0.000 description 3
- 229920002988 biodegradable polymer Polymers 0.000 description 3
- 239000004621 biodegradable polymer Substances 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- 239000007795 chemical reaction product Substances 0.000 description 3
- 238000011097 chromatography purification Methods 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
- 239000012230 colorless oil Substances 0.000 description 3
- 238000013270 controlled release Methods 0.000 description 3
- 235000019325 ethyl cellulose Nutrition 0.000 description 3
- 229920001249 ethyl cellulose Polymers 0.000 description 3
- 239000012894 fetal calf serum Substances 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 235000003599 food sweetener Nutrition 0.000 description 3
- 210000001035 gastrointestinal tract Anatomy 0.000 description 3
- 239000008187 granular material Substances 0.000 description 3
- 238000009434 installation Methods 0.000 description 3
- FZWBNHMXJMCXLU-BLAUPYHCSA-N isomaltotriose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@@H](OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O)O1 FZWBNHMXJMCXLU-BLAUPYHCSA-N 0.000 description 3
- 210000004698 lymphocyte Anatomy 0.000 description 3
- 235000019359 magnesium stearate Nutrition 0.000 description 3
- 239000012528 membrane Substances 0.000 description 3
- 230000007935 neutral effect Effects 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 239000012188 paraffin wax Substances 0.000 description 3
- 230000000144 pharmacologic effect Effects 0.000 description 3
- 210000003800 pharynx Anatomy 0.000 description 3
- 229920000570 polyether Polymers 0.000 description 3
- 229920000193 polymethacrylate Polymers 0.000 description 3
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 229940100486 rice starch Drugs 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 238000007920 subcutaneous administration Methods 0.000 description 3
- 239000004094 surface-active agent Substances 0.000 description 3
- 239000003765 sweetening agent Substances 0.000 description 3
- 150000003626 triacylglycerols Chemical class 0.000 description 3
- 150000003673 urethanes Chemical class 0.000 description 3
- 239000008215 water for injection Substances 0.000 description 3
- KISVATOISQDZJU-UHFFFAOYSA-N (1-benzhydrylazetidin-3-yl)methanamine Chemical compound C1C(CN)CN1C(C=1C=CC=CC=1)C1=CC=CC=C1 KISVATOISQDZJU-UHFFFAOYSA-N 0.000 description 2
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 2
- JUEJWLBPWQMLHR-UHFFFAOYSA-N 1-benzhydrylpiperidine-3-carboxylic acid;hydrochloride Chemical compound Cl.C1C(C(=O)O)CCCN1C(C=1C=CC=CC=1)C1=CC=CC=C1 JUEJWLBPWQMLHR-UHFFFAOYSA-N 0.000 description 2
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 2
- UXFPMNSYBVPROG-UHFFFAOYSA-N 3-(1-benzylpiperidin-4-yl)oxypropan-1-amine Chemical compound C1CC(OCCCN)CCN1CC1=CC=CC=C1 UXFPMNSYBVPROG-UHFFFAOYSA-N 0.000 description 2
- IHUYMRIGAVJQHJ-UHFFFAOYSA-N 4-(1-benzylpiperidin-3-yl)butan-1-amine Chemical compound C1C(CCCCN)CCCN1CC1=CC=CC=C1 IHUYMRIGAVJQHJ-UHFFFAOYSA-N 0.000 description 2
- KCIUHAPGAMLYAO-UHFFFAOYSA-N 4-(1-benzylpiperidin-3-ylidene)butanenitrile Chemical compound C1C(=CCCC#N)CCCN1CC1=CC=CC=C1 KCIUHAPGAMLYAO-UHFFFAOYSA-N 0.000 description 2
- 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 description 2
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 2
- 208000024827 Alzheimer disease Diseases 0.000 description 2
- 235000003911 Arachis Nutrition 0.000 description 2
- 244000105624 Arachis hypogaea Species 0.000 description 2
- UPVYLEZQZSHBQM-UHFFFAOYSA-N CC1CCN(C(=O)C(C2=CC=CC=C2)C2=CC=CC=C2)CC1 Chemical compound CC1CCN(C(=O)C(C2=CC=CC=C2)C2=CC=CC=C2)CC1 UPVYLEZQZSHBQM-UHFFFAOYSA-N 0.000 description 2
- GZFLYDKIUYQDOQ-UHFFFAOYSA-N CC=C1CCN(CC2=CC=CC=C2)CC1 Chemical compound CC=C1CCN(CC2=CC=CC=C2)CC1 GZFLYDKIUYQDOQ-UHFFFAOYSA-N 0.000 description 2
- YZMGZTAVAVEPDT-UHFFFAOYSA-N CCC1CC2CCC(C1)N2C(C1=CC=CC=C1)C1=CC=CC=C1 Chemical compound CCC1CC2CCC(C1)N2C(C1=CC=CC=C1)C1=CC=CC=C1 YZMGZTAVAVEPDT-UHFFFAOYSA-N 0.000 description 2
- DZEKXNZRIOWTHG-UHFFFAOYSA-N CCC1CCN(C(=O)OC(C)(C)C)CC1 Chemical compound CCC1CCN(C(=O)OC(C)(C)C)CC1 DZEKXNZRIOWTHG-UHFFFAOYSA-N 0.000 description 2
- YRPDCERXKOLAFN-UHFFFAOYSA-N CCC1CCN(C(C)=O)CC1 Chemical compound CCC1CCN(C(C)=O)CC1 YRPDCERXKOLAFN-UHFFFAOYSA-N 0.000 description 2
- ZRNBMNUBFPDZMP-UHFFFAOYSA-N CCC1CCN(SO(O)C2=CC3=CC=CC=C3C=C2)CC1 Chemical compound CCC1CCN(SO(O)C2=CC3=CC=CC=C3C=C2)CC1 ZRNBMNUBFPDZMP-UHFFFAOYSA-N 0.000 description 2
- UANYSFUTELNAFR-UHFFFAOYSA-N CCCCC1CCCN(C(C2=CC=CC=C2)(C2=CC=CC=C2)C2=CC=CC=C2)C1 Chemical compound CCCCC1CCCN(C(C2=CC=CC=C2)(C2=CC=CC=C2)C2=CC=CC=C2)C1 UANYSFUTELNAFR-UHFFFAOYSA-N 0.000 description 2
- PDZNEEDNVIHBOL-UHFFFAOYSA-N CCCCC1CCCN(CC2=CC=CC=C2)C1 Chemical compound CCCCC1CCCN(CC2=CC=CC=C2)C1 PDZNEEDNVIHBOL-UHFFFAOYSA-N 0.000 description 2
- DNZFQWJHRJZRKT-UHFFFAOYSA-N CCCCC1CCN(C(=O)C(F)(F)F)CC1 Chemical compound CCCCC1CCN(C(=O)C(F)(F)F)CC1 DNZFQWJHRJZRKT-UHFFFAOYSA-N 0.000 description 2
- RYOAKMFUZAIQRK-UHFFFAOYSA-N CCCCC1CCN(C(=O)C2=C(C3=CC=CC=C3)C=CC=C2)CC1 Chemical compound CCCCC1CCN(C(=O)C2=C(C3=CC=CC=C3)C=CC=C2)CC1 RYOAKMFUZAIQRK-UHFFFAOYSA-N 0.000 description 2
- WPAMLBQYKFGFDQ-UHFFFAOYSA-N CCCCC1CCN(C(=O)C2=CC3=CC=CC=C3C=C2)CC1 Chemical compound CCCCC1CCN(C(=O)C2=CC3=CC=CC=C3C=C2)CC1 WPAMLBQYKFGFDQ-UHFFFAOYSA-N 0.000 description 2
- XJTZBWWHNZYRLB-UHFFFAOYSA-N CCCCC1CCN(C(=O)C2=CC=C(C3=CC=CC=C3)C=C2)CC1 Chemical compound CCCCC1CCN(C(=O)C2=CC=C(C3=CC=CC=C3)C=C2)CC1 XJTZBWWHNZYRLB-UHFFFAOYSA-N 0.000 description 2
- QYLWFPHHTFHISH-UHFFFAOYSA-N CCCCC1CCN(C(=O)C2=CC=CN=C2)CC1 Chemical compound CCCCC1CCN(C(=O)C2=CC=CN=C2)CC1 QYLWFPHHTFHISH-UHFFFAOYSA-N 0.000 description 2
- FGZMNPCJETYFGF-UHFFFAOYSA-N CCCCC1CCN(C(=O)C2=COC3=C(C=CC=C3)C2=O)CC1 Chemical compound CCCCC1CCN(C(=O)C2=COC3=C(C=CC=C3)C2=O)CC1 FGZMNPCJETYFGF-UHFFFAOYSA-N 0.000 description 2
- FPVQGMRMYUFDIJ-UHFFFAOYSA-N CCCCC1CCN(C(=O)C2=NC3=CC=CC=C3N=C2)CC1 Chemical compound CCCCC1CCN(C(=O)C2=NC3=CC=CC=C3N=C2)CC1 FPVQGMRMYUFDIJ-UHFFFAOYSA-N 0.000 description 2
- UZSDCHXZWJRWGU-UHFFFAOYSA-N CCCCC1CCN(C(=O)C2CC2)CC1 Chemical compound CCCCC1CCN(C(=O)C2CC2)CC1 UZSDCHXZWJRWGU-UHFFFAOYSA-N 0.000 description 2
- ISZVRCVTQDRVIE-UHFFFAOYSA-N CCCCC1CCN(C(=O)CC2=CC=CC=C2)CC1 Chemical compound CCCCC1CCN(C(=O)CC2=CC=CC=C2)CC1 ISZVRCVTQDRVIE-UHFFFAOYSA-N 0.000 description 2
- VJAFMJSIDMZPAL-UHFFFAOYSA-N CCCCC1CCN(C(=O)CN2C(=O)SC3=C2C=C(Cl)C=N3)CC1 Chemical compound CCCCC1CCN(C(=O)CN2C(=O)SC3=C2C=C(Cl)C=N3)CC1 VJAFMJSIDMZPAL-UHFFFAOYSA-N 0.000 description 2
- DKHRLGWLELZLTB-UHFFFAOYSA-N CCCCC1CCN(C(=O)N2C3=C(C=CC=C3)CCC3=C2C=CC=C3)CC1 Chemical compound CCCCC1CCN(C(=O)N2C3=C(C=CC=C3)CCC3=C2C=CC=C3)CC1 DKHRLGWLELZLTB-UHFFFAOYSA-N 0.000 description 2
- QROIBIFKORUZNR-UHFFFAOYSA-N CCCCC1CCN(C(=O)N2CC3=C(C=CC=C3)CC3=C2C=CC=C3)CC1 Chemical compound CCCCC1CCN(C(=O)N2CC3=C(C=CC=C3)CC3=C2C=CC=C3)CC1 QROIBIFKORUZNR-UHFFFAOYSA-N 0.000 description 2
- IDKHCFJWDZTLOK-UHFFFAOYSA-N CCCCC1CCN(C(=O)N2CCC3=C2C=CC=C3)CC1 Chemical compound CCCCC1CCN(C(=O)N2CCC3=C2C=CC=C3)CC1 IDKHCFJWDZTLOK-UHFFFAOYSA-N 0.000 description 2
- BVXAMJGSLGPZQD-UHFFFAOYSA-N CCCCC1CCN(C(=O)OC)CC1 Chemical compound CCCCC1CCN(C(=O)OC)CC1 BVXAMJGSLGPZQD-UHFFFAOYSA-N 0.000 description 2
- ASYISVMQVPNRNT-UHFFFAOYSA-N CCCCC1CCN(C(C2=CC=C(Cl)C=C2)C2=CC=C(Cl)C=C2)CC1 Chemical compound CCCCC1CCN(C(C2=CC=C(Cl)C=C2)C2=CC=C(Cl)C=C2)CC1 ASYISVMQVPNRNT-UHFFFAOYSA-N 0.000 description 2
- CGEPYNPPYZWNBD-UHFFFAOYSA-N CCCCC1CCN(C2=NC=NC3=C2C(C)=CS3)CC1 Chemical compound CCCCC1CCN(C2=NC=NC3=C2C(C)=CS3)CC1 CGEPYNPPYZWNBD-UHFFFAOYSA-N 0.000 description 2
- IGFFEAVBUVYFMF-UHFFFAOYSA-N CCCCC1CCN(C2C3=C(C=CC=C3)CCC3=C2C=CC=C3)CC1 Chemical compound CCCCC1CCN(C2C3=C(C=CC=C3)CCC3=C2C=CC=C3)CC1 IGFFEAVBUVYFMF-UHFFFAOYSA-N 0.000 description 2
- DEXSKJMVCFRLQL-UHFFFAOYSA-N CCCCC1CCN(C2C3=CC=CC=C3C3=C2C=CC=C3)CC1 Chemical compound CCCCC1CCN(C2C3=CC=CC=C3C3=C2C=CC=C3)CC1 DEXSKJMVCFRLQL-UHFFFAOYSA-N 0.000 description 2
- YNIUFBJWQITFIH-UHFFFAOYSA-N CCCCC1CCN(SO(C)O)CC1 Chemical compound CCCCC1CCN(SO(C)O)CC1 YNIUFBJWQITFIH-UHFFFAOYSA-N 0.000 description 2
- ZGZHMLXQOVVPFE-UHFFFAOYSA-N CCCCC1CCN(SO(O)C2=C(C)C3=C(C=CC(Cl)=C3)S2)CC1 Chemical compound CCCCC1CCN(SO(O)C2=C(C)C3=C(C=CC(Cl)=C3)S2)CC1 ZGZHMLXQOVVPFE-UHFFFAOYSA-N 0.000 description 2
- KINWXAKOBYQRIN-UHFFFAOYSA-N CCCCC1CCN(SO(O)C2=C(Cl)N=C3SC=CN32)CC1 Chemical compound CCCCC1CCN(SO(O)C2=C(Cl)N=C3SC=CN32)CC1 KINWXAKOBYQRIN-UHFFFAOYSA-N 0.000 description 2
- PDNBXDZIUKNLTB-UHFFFAOYSA-N CCCCC1CCN(SO(O)C2=CC=C(C)C=C2)CC1 Chemical compound CCCCC1CCN(SO(O)C2=CC=C(C)C=C2)CC1 PDNBXDZIUKNLTB-UHFFFAOYSA-N 0.000 description 2
- DWNZELLEOGHJAU-UHFFFAOYSA-N CCCCCCNC(=O)C1CCCN(C(C2=CC=CC=C2)C2=CC=CC=C2)C1 Chemical compound CCCCCCNC(=O)C1CCCN(C(C2=CC=CC=C2)C2=CC=CC=C2)C1 DWNZELLEOGHJAU-UHFFFAOYSA-N 0.000 description 2
- PCTPNBVNHKPKKG-UHFFFAOYSA-N CCCOC1CCN(C(C2=CC=CC=C2)C2=CC=CC=C2)CC1 Chemical compound CCCOC1CCN(C(C2=CC=CC=C2)C2=CC=CC=C2)CC1 PCTPNBVNHKPKKG-UHFFFAOYSA-N 0.000 description 2
- GWRYDDXEFLJANT-UHFFFAOYSA-N CCCOC1CCN(CC2=CC=CC=C2)CC1 Chemical compound CCCOC1CCN(CC2=CC=CC=C2)CC1 GWRYDDXEFLJANT-UHFFFAOYSA-N 0.000 description 2
- VZFPHLFPAUVQBT-UHFFFAOYSA-N CCCOCC1CCN(C(C2=CC=CC=C2)C2=CC=CC=C2)CC1 Chemical compound CCCOCC1CCN(C(C2=CC=CC=C2)C2=CC=CC=C2)CC1 VZFPHLFPAUVQBT-UHFFFAOYSA-N 0.000 description 2
- HVKPAFBQSBNNEE-UHFFFAOYSA-N CCNC(=O)OC1CN(C(C2=CC=CC=C2)C2=CC=CC=C2)C1 Chemical compound CCNC(=O)OC1CN(C(C2=CC=CC=C2)C2=CC=CC=C2)C1 HVKPAFBQSBNNEE-UHFFFAOYSA-N 0.000 description 2
- MZJFKQUHZHVPTK-UHFFFAOYSA-N CCNC1CCN(C(C2=CC=CC=C2)C2=CC=CC=C2)CC1 Chemical compound CCNC1CCN(C(C2=CC=CC=C2)C2=CC=CC=C2)CC1 MZJFKQUHZHVPTK-UHFFFAOYSA-N 0.000 description 2
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 2
- GHVNFZFCNZKVNT-UHFFFAOYSA-N Decanoic acid Natural products CCCCCCCCCC(O)=O GHVNFZFCNZKVNT-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
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 2
- 241000792859 Enema Species 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N Lactic Acid Natural products CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000004166 Lanolin Substances 0.000 description 2
- 206010025323 Lymphomas Diseases 0.000 description 2
- QPJVMBTYPHYUOC-UHFFFAOYSA-N Methyl benzoate Natural products COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 description 2
- NWIBSHFKIJFRCO-WUDYKRTCSA-N Mytomycin Chemical compound C1N2C(C(C(C)=C(N)C3=O)=O)=C3[C@@H](COC(N)=O)[C@@]2(OC)[C@@H]2[C@H]1N2 NWIBSHFKIJFRCO-WUDYKRTCSA-N 0.000 description 2
- LDQSDLVQUXPSIT-UHFFFAOYSA-N NC(=O)C1CCN(C(C2=CC=CC=C2)C2=CC=CC=C2)CC1 Chemical compound NC(=O)C1CCN(C(C2=CC=CC=C2)C2=CC=CC=C2)CC1 LDQSDLVQUXPSIT-UHFFFAOYSA-N 0.000 description 2
- 239000005642 Oleic acid Substances 0.000 description 2
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 239000007868 Raney catalyst Substances 0.000 description 2
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 2
- 229910000564 Raney nickel Inorganic materials 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 239000004147 Sorbitan trioleate Substances 0.000 description 2
- PRXRUNOAOLTIEF-ADSICKODSA-N Sorbitan trioleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@@H](OC(=O)CCCCCCC\C=C/CCCCCCCC)[C@H]1OC[C@H](O)[C@H]1OC(=O)CCCCCCC\C=C/CCCCCCCC PRXRUNOAOLTIEF-ADSICKODSA-N 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- 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 2
- NKANXQFJJICGDU-QPLCGJKRSA-N Tamoxifen Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCCN(C)C)=CC=1)/C1=CC=CC=C1 NKANXQFJJICGDU-QPLCGJKRSA-N 0.000 description 2
- DOOTYTYQINUNNV-UHFFFAOYSA-N Triethyl citrate Chemical compound CCOC(=O)CC(O)(C(=O)OCC)CC(=O)OCC DOOTYTYQINUNNV-UHFFFAOYSA-N 0.000 description 2
- 241000209140 Triticum Species 0.000 description 2
- 235000021307 Triticum Nutrition 0.000 description 2
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 2
- RJURFGZVJUQBHK-UHFFFAOYSA-N actinomycin D Natural products CC1OC(=O)C(C(C)C)N(C)C(=O)CN(C)C(=O)C2CCCN2C(=O)C(C(C)C)NC(=O)C1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)NC4C(=O)NC(C(N5CCCC5C(=O)N(C)CC(=O)N(C)C(C(C)C)C(=O)OC4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-UHFFFAOYSA-N 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 230000003266 anti-allergic effect Effects 0.000 description 2
- 235000006708 antioxidants Nutrition 0.000 description 2
- 239000000227 bioadhesive Substances 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical class [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 2
- 239000004202 carbamide Substances 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 2
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 2
- 239000004359 castor oil Substances 0.000 description 2
- 235000019438 castor oil Nutrition 0.000 description 2
- 125000002091 cationic group Chemical group 0.000 description 2
- 238000003776 cleavage reaction Methods 0.000 description 2
- 239000003086 colorant Substances 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 230000001472 cytotoxic effect Effects 0.000 description 2
- 230000003247 decreasing effect Effects 0.000 description 2
- 235000013681 dietary sucrose Nutrition 0.000 description 2
- 231100000673 dose–response relationship Toxicity 0.000 description 2
- 239000006196 drop Substances 0.000 description 2
- 239000003995 emulsifying agent Substances 0.000 description 2
- 239000007920 enema Substances 0.000 description 2
- 229940095399 enema Drugs 0.000 description 2
- 150000002191 fatty alcohols Chemical class 0.000 description 2
- 235000011389 fruit/vegetable juice Nutrition 0.000 description 2
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 2
- 239000001963 growth medium Substances 0.000 description 2
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 2
- 239000007972 injectable composition Substances 0.000 description 2
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 2
- 235000019388 lanolin Nutrition 0.000 description 2
- 239000000787 lecithin Substances 0.000 description 2
- 235000010445 lecithin Nutrition 0.000 description 2
- 239000002502 liposome Substances 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- 208000014018 liver neoplasm Diseases 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- POULHZVOKOAJMA-UHFFFAOYSA-N methyl undecanoic acid Natural products CCCCCCCCCCCC(O)=O POULHZVOKOAJMA-UHFFFAOYSA-N 0.000 description 2
- 210000003097 mucus Anatomy 0.000 description 2
- ABNUGIPWBGEPAS-UHFFFAOYSA-N n-[4-(1-benzhydrylpiperidin-4-yl)butyl]-5-pyridin-3-ylpenta-2,4-dienamide Chemical compound C=1C=CN=CC=1C=CC=CC(=O)NCCCCC(CC1)CCN1C(C=1C=CC=CC=1)C1=CC=CC=C1 ABNUGIPWBGEPAS-UHFFFAOYSA-N 0.000 description 2
- 235000015097 nutrients Nutrition 0.000 description 2
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 2
- 210000000056 organ Anatomy 0.000 description 2
- 230000003204 osmotic effect Effects 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 230000010412 perfusion Effects 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 2
- 239000010452 phosphate Substances 0.000 description 2
- 150000003904 phospholipids Chemical class 0.000 description 2
- 229920003023 plastic Polymers 0.000 description 2
- 239000004033 plastic Substances 0.000 description 2
- 229920001308 poly(aminoacid) Polymers 0.000 description 2
- 229920000747 poly(lactic acid) Polymers 0.000 description 2
- 239000008389 polyethoxylated castor oil Substances 0.000 description 2
- 239000004626 polylactic acid Substances 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 239000011347 resin Substances 0.000 description 2
- 229920005989 resin Polymers 0.000 description 2
- 239000003340 retarding agent Substances 0.000 description 2
- 230000007017 scission Effects 0.000 description 2
- 235000012239 silicon dioxide Nutrition 0.000 description 2
- 210000000813 small intestine Anatomy 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 235000010265 sodium sulphite Nutrition 0.000 description 2
- 235000019337 sorbitan trioleate Nutrition 0.000 description 2
- 229960000391 sorbitan trioleate Drugs 0.000 description 2
- 238000001179 sorption measurement Methods 0.000 description 2
- 239000006190 sub-lingual tablet Substances 0.000 description 2
- 229960004793 sucrose Drugs 0.000 description 2
- 238000007910 systemic administration Methods 0.000 description 2
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 2
- HHOFUZXTBHKGTC-UHFFFAOYSA-N tert-butyl 4-(4-aminobutyl)piperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(CCCCN)CC1 HHOFUZXTBHKGTC-UHFFFAOYSA-N 0.000 description 2
- GVOGVPFQDCQZNP-UHFFFAOYSA-N tert-butyl 4-(4-hydroxybutyl)piperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(CCCCO)CC1 GVOGVPFQDCQZNP-UHFFFAOYSA-N 0.000 description 2
- BMHPRMXSKRSFEW-UHFFFAOYSA-N tert-butyl 4-[4-(1,3-dioxoisoindol-2-yl)butyl]piperidine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1CCCCN1C(=O)C2=CC=CC=C2C1=O BMHPRMXSKRSFEW-UHFFFAOYSA-N 0.000 description 2
- VGGCSKJNFCVWFW-UHFFFAOYSA-N tert-butyl 4-[4-(3-pyridin-3-ylprop-2-enoylamino)butyl]piperidine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1CCCCNC(=O)C=CC1=CC=CN=C1 VGGCSKJNFCVWFW-UHFFFAOYSA-N 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 239000001069 triethyl citrate Substances 0.000 description 2
- 235000013769 triethyl citrate Nutrition 0.000 description 2
- VMYFZRTXGLUXMZ-UHFFFAOYSA-N triethyl citrate Natural products CCOC(=O)C(O)(C(=O)OCC)C(=O)OCC VMYFZRTXGLUXMZ-UHFFFAOYSA-N 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 2
- 238000002604 ultrasonography Methods 0.000 description 2
- 235000013343 vitamin Nutrition 0.000 description 2
- 239000011782 vitamin Substances 0.000 description 2
- 229940088594 vitamin Drugs 0.000 description 2
- 229930003231 vitamin Natural products 0.000 description 2
- DIGQNXIGRZPYDK-WKSCXVIASA-N (2R)-6-amino-2-[[2-[[(2S)-2-[[2-[[(2R)-2-[[(2S)-2-[[(2R,3S)-2-[[2-[[(2S)-2-[[2-[[(2S)-2-[[(2S)-2-[[(2R)-2-[[(2S,3S)-2-[[(2R)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[2-[[(2S)-2-[[(2R)-2-[[2-[[2-[[2-[(2-amino-1-hydroxyethylidene)amino]-3-carboxy-1-hydroxypropylidene]amino]-1-hydroxy-3-sulfanylpropylidene]amino]-1-hydroxyethylidene]amino]-1-hydroxy-3-sulfanylpropylidene]amino]-1,3-dihydroxypropylidene]amino]-1-hydroxyethylidene]amino]-1-hydroxypropylidene]amino]-1,3-dihydroxypropylidene]amino]-1,3-dihydroxypropylidene]amino]-1-hydroxy-3-sulfanylpropylidene]amino]-1,3-dihydroxybutylidene]amino]-1-hydroxy-3-sulfanylpropylidene]amino]-1-hydroxypropylidene]amino]-1,3-dihydroxypropylidene]amino]-1-hydroxyethylidene]amino]-1,5-dihydroxy-5-iminopentylidene]amino]-1-hydroxy-3-sulfanylpropylidene]amino]-1,3-dihydroxybutylidene]amino]-1-hydroxy-3-sulfanylpropylidene]amino]-1,3-dihydroxypropylidene]amino]-1-hydroxyethylidene]amino]-1-hydroxy-3-sulfanylpropylidene]amino]-1-hydroxyethylidene]amino]hexanoic acid Chemical compound C[C@@H]([C@@H](C(=N[C@@H](CS)C(=N[C@@H](C)C(=N[C@@H](CO)C(=NCC(=N[C@@H](CCC(=N)O)C(=NC(CS)C(=N[C@H]([C@H](C)O)C(=N[C@H](CS)C(=N[C@H](CO)C(=NCC(=N[C@H](CS)C(=NCC(=N[C@H](CCCCN)C(=O)O)O)O)O)O)O)O)O)O)O)O)O)O)O)N=C([C@H](CS)N=C([C@H](CO)N=C([C@H](CO)N=C([C@H](C)N=C(CN=C([C@H](CO)N=C([C@H](CS)N=C(CN=C(C(CS)N=C(C(CC(=O)O)N=C(CN)O)O)O)O)O)O)O)O)O)O)O)O DIGQNXIGRZPYDK-WKSCXVIASA-N 0.000 description 1
- QDZOEBFLNHCSSF-PFFBOGFISA-N (2S)-2-[[(2R)-2-[[(2S)-1-[(2S)-6-amino-2-[[(2S)-1-[(2R)-2-amino-5-carbamimidamidopentanoyl]pyrrolidine-2-carbonyl]amino]hexanoyl]pyrrolidine-2-carbonyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-N-[(2R)-1-[[(2S)-1-[[(2R)-1-[[(2S)-1-[[(2S)-1-amino-4-methyl-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]pentanediamide Chemical compound C([C@@H](C(=O)N[C@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(N)=O)NC(=O)[C@@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](N)CCCNC(N)=N)C1=CC=CC=C1 QDZOEBFLNHCSSF-PFFBOGFISA-N 0.000 description 1
- JNYAEWCLZODPBN-JGWLITMVSA-N (2r,3r,4s)-2-[(1r)-1,2-dihydroxyethyl]oxolane-3,4-diol Chemical compound OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O JNYAEWCLZODPBN-JGWLITMVSA-N 0.000 description 1
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 1
- BLUGYPPOFIHFJS-UUFHNPECSA-N (2s)-n-[(2s)-1-[[(3r,4s,5s)-3-methoxy-1-[(2s)-2-[(1r,2r)-1-methoxy-2-methyl-3-oxo-3-[[(1s)-2-phenyl-1-(1,3-thiazol-2-yl)ethyl]amino]propyl]pyrrolidin-1-yl]-5-methyl-1-oxoheptan-4-yl]-methylamino]-3-methyl-1-oxobutan-2-yl]-3-methyl-2-(methylamino)butanamid Chemical compound CN[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N(C)[C@@H]([C@@H](C)CC)[C@H](OC)CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](C=1SC=CN=1)CC1=CC=CC=C1 BLUGYPPOFIHFJS-UUFHNPECSA-N 0.000 description 1
- CXPBQHQMQFYHBW-UHFFFAOYSA-N (4-benzhydrylmorpholin-2-yl)methanamine Chemical compound C1COC(CN)CN1C(C=1C=CC=CC=1)C1=CC=CC=C1 CXPBQHQMQFYHBW-UHFFFAOYSA-N 0.000 description 1
- FDKXTQMXEQVLRF-ZHACJKMWSA-N (E)-dacarbazine Chemical compound CN(C)\N=N\c1[nH]cnc1C(N)=O FDKXTQMXEQVLRF-ZHACJKMWSA-N 0.000 description 1
- RJEPYCVXMBLLDR-RRABGKBLSA-N (e)-n-[2-(1-benzylpiperidin-4-yl)ethyl]-3-pyridin-2-ylprop-2-enamide;hydrochloride Chemical compound Cl.C=1C=CC=NC=1/C=C/C(=O)NCCC(CC1)CCN1CC1=CC=CC=C1 RJEPYCVXMBLLDR-RRABGKBLSA-N 0.000 description 1
- FQUYSHZXSKYCSY-UHFFFAOYSA-N 1,4-diazepane Chemical group C1CNCCNC1 FQUYSHZXSKYCSY-UHFFFAOYSA-N 0.000 description 1
- 102100025573 1-alkyl-2-acetylglycerophosphocholine esterase Human genes 0.000 description 1
- UUTRFWITTHKQKD-UHFFFAOYSA-N 1-benzhydryl-n-[6-(3-pyridin-3-ylprop-2-enoylamino)hexyl]piperidine-3-carboxamide Chemical compound C=1C=CN=CC=1C=CC(=O)NCCCCCCNC(=O)C(C1)CCCN1C(C=1C=CC=CC=1)C1=CC=CC=C1 UUTRFWITTHKQKD-UHFFFAOYSA-N 0.000 description 1
- IXMOEAHDRKNAAG-UHFFFAOYSA-N 1-benzhydrylazetidine-3-carbonitrile Chemical compound C1C(C#N)CN1C(C=1C=CC=CC=1)C1=CC=CC=C1 IXMOEAHDRKNAAG-UHFFFAOYSA-N 0.000 description 1
- BBQQULRBTOMLTC-UHFFFAOYSA-N 1-benzylpiperidin-3-one Chemical compound C1C(=O)CCCN1CC1=CC=CC=C1 BBQQULRBTOMLTC-UHFFFAOYSA-N 0.000 description 1
- VFWCMGCRMGJXDK-UHFFFAOYSA-N 1-chlorobutane Chemical compound CCCCCl VFWCMGCRMGJXDK-UHFFFAOYSA-N 0.000 description 1
- AXTGDCSMTYGJND-UHFFFAOYSA-N 1-dodecylazepan-2-one Chemical compound CCCCCCCCCCCCN1CCCCCC1=O AXTGDCSMTYGJND-UHFFFAOYSA-N 0.000 description 1
- BDQNKCYCTYYMAA-UHFFFAOYSA-N 1-isocyanatonaphthalene Chemical compound C1=CC=C2C(N=C=O)=CC=CC2=C1 BDQNKCYCTYYMAA-UHFFFAOYSA-N 0.000 description 1
- LYGVSZXMMRLJPF-UHFFFAOYSA-N 11-chloro-6,11-dihydrobenzo[c][1]benzothiepine Chemical compound C1SC2=CC=CC=C2C(Cl)C2=CC=CC=C21 LYGVSZXMMRLJPF-UHFFFAOYSA-N 0.000 description 1
- DGHHQBMTXTWTJV-BQAIUKQQSA-N 119413-54-6 Chemical compound Cl.C1=C(O)C(CN(C)C)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 DGHHQBMTXTWTJV-BQAIUKQQSA-N 0.000 description 1
- JVSFQJZRHXAUGT-UHFFFAOYSA-N 2,2-dimethylpropanoyl chloride Chemical compound CC(C)(C)C(Cl)=O JVSFQJZRHXAUGT-UHFFFAOYSA-N 0.000 description 1
- MSYLETHDEIJMAF-UHFFFAOYSA-N 2,2-diphenylacetyl chloride Chemical compound C=1C=CC=CC=1C(C(=O)Cl)C1=CC=CC=C1 MSYLETHDEIJMAF-UHFFFAOYSA-N 0.000 description 1
- MZBVNYACSSGXID-UHFFFAOYSA-N 2,3,4,5-tetrahydro-1h-1-benzazepine Chemical compound N1CCCCC2=CC=CC=C21 MZBVNYACSSGXID-UHFFFAOYSA-N 0.000 description 1
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N 2-Propenoic acid Natural products OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- YEYKMVJDLWJFOA-UHFFFAOYSA-N 2-propoxyethanol Chemical compound CCCOCCO YEYKMVJDLWJFOA-UHFFFAOYSA-N 0.000 description 1
- XTUAIKRVIJDPCZ-UHFFFAOYSA-N 3-(1-benzylpiperidin-4-yl)oxypropanenitrile Chemical compound C1CC(OCCC#N)CCN1CC1=CC=CC=C1 XTUAIKRVIJDPCZ-UHFFFAOYSA-N 0.000 description 1
- PAOHMIPLGDOHBB-UHFFFAOYSA-M 3-cyanopropyl(triphenyl)phosphanium;bromide Chemical compound [Br-].C=1C=CC=CC=1[P+](C=1C=CC=CC=1)(CCCC#N)C1=CC=CC=C1 PAOHMIPLGDOHBB-UHFFFAOYSA-M 0.000 description 1
- BZISNWGGPWSXTK-UHFFFAOYSA-N 3-hydroxypropyl benzoate Chemical compound OCCCOC(=O)C1=CC=CC=C1 BZISNWGGPWSXTK-UHFFFAOYSA-N 0.000 description 1
- LKDFTXDJKHGCAC-UHFFFAOYSA-N 3-pyridin-2-ylprop-2-enoic acid Chemical compound OC(=O)C=CC1=CC=CC=N1 LKDFTXDJKHGCAC-UHFFFAOYSA-N 0.000 description 1
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 1
- WPQJAHKNOGSQFS-UHFFFAOYSA-N 4-(1-benzhydrylpiperidin-4-yl)butan-1-amine Chemical compound C1CC(CCCCN)CCN1C(C=1C=CC=CC=1)C1=CC=CC=C1 WPQJAHKNOGSQFS-UHFFFAOYSA-N 0.000 description 1
- VZKFZHMCAPEJSE-UHFFFAOYSA-N 4-piperidin-4-ylbutan-1-ol;hydrochloride Chemical compound Cl.OCCCCC1CCNCC1 VZKFZHMCAPEJSE-UHFFFAOYSA-N 0.000 description 1
- CCEWTWCJOWECLY-UHFFFAOYSA-N 5-pyridin-3-ylpenta-2,4-dienoic acid Chemical compound OC(=O)C=CC=CC1=CC=CN=C1 CCEWTWCJOWECLY-UHFFFAOYSA-N 0.000 description 1
- STQGQHZAVUOBTE-UHFFFAOYSA-N 7-Cyan-hept-2t-en-4,6-diinsaeure Natural products C1=2C(O)=C3C(=O)C=4C(OC)=CC=CC=4C(=O)C3=C(O)C=2CC(O)(C(C)=O)CC1OC1CC(N)C(O)C(C)O1 STQGQHZAVUOBTE-UHFFFAOYSA-N 0.000 description 1
- GJCOSYZMQJWQCA-UHFFFAOYSA-N 9H-xanthene Chemical compound C1=CC=C2CC3=CC=CC=C3OC2=C1 GJCOSYZMQJWQCA-UHFFFAOYSA-N 0.000 description 1
- 208000007934 ACTH-independent macronodular adrenal hyperplasia Diseases 0.000 description 1
- 102100033350 ATP-dependent translocase ABCB1 Human genes 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 1
- 206010000830 Acute leukaemia Diseases 0.000 description 1
- 108010088751 Albumins Proteins 0.000 description 1
- 102000009027 Albumins Human genes 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- 208000000044 Amnesia Diseases 0.000 description 1
- 208000031091 Amnestic disease Diseases 0.000 description 1
- 102000001381 Arachidonate 5-Lipoxygenase Human genes 0.000 description 1
- 108010093579 Arachidonate 5-lipoxygenase Proteins 0.000 description 1
- 108010024976 Asparaginase Proteins 0.000 description 1
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- 108010006654 Bleomycin Proteins 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- FIYKVKLFCGGMKD-NSCUHMNNSA-N C/C=C/CC1CCN(C(C2=CC=CC=C2)C2=CC=CC=C2)CC1 Chemical compound C/C=C/CC1CCN(C(C2=CC=CC=C2)C2=CC=CC=C2)CC1 FIYKVKLFCGGMKD-NSCUHMNNSA-N 0.000 description 1
- QQONPFPTGQHPMA-UHFFFAOYSA-N C=CC Chemical compound C=CC QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 1
- FSVDALTVDDWHNW-UHFFFAOYSA-N C=CC(O)C(F)F Chemical compound C=CC(O)C(F)F FSVDALTVDDWHNW-UHFFFAOYSA-N 0.000 description 1
- LXKVRSCRNWIJPR-UHFFFAOYSA-N C=CC(O)CF Chemical compound C=CC(O)CF LXKVRSCRNWIJPR-UHFFFAOYSA-N 0.000 description 1
- JGIYZRBDBRYOFW-UHFFFAOYSA-N C=CCOC(=O)N1CCC(CCCC)CC1 Chemical compound C=CCOC(=O)N1CCC(CCCC)CC1 JGIYZRBDBRYOFW-UHFFFAOYSA-N 0.000 description 1
- NZOVJSHVWFGJFE-UHFFFAOYSA-N CC#CCC1CCN(C(=O)OC(C)(C)C)CC1 Chemical compound CC#CCC1CCN(C(=O)OC(C)(C)C)CC1 NZOVJSHVWFGJFE-UHFFFAOYSA-N 0.000 description 1
- KPYYRTWSOAZOOG-UHFFFAOYSA-N CC#CCC1CCN(C(C2=CC=CC=C2)C2=CC=CC=C2)CC1 Chemical compound CC#CCC1CCN(C(C2=CC=CC=C2)C2=CC=CC=C2)CC1 KPYYRTWSOAZOOG-UHFFFAOYSA-N 0.000 description 1
- XHZDZYQPPMQJJR-CLTKARDFSA-N CC/C=C\C1CCN(C(=O)C2=CC=CC=C2)CC1 Chemical compound CC/C=C\C1CCN(C(=O)C2=CC=CC=C2)CC1 XHZDZYQPPMQJJR-CLTKARDFSA-N 0.000 description 1
- OPNDCHTUSBUNIE-UHFFFAOYSA-N CC1=CC=C(O(O)SN2CCC(C)CC2)C=C1 Chemical compound CC1=CC=C(O(O)SN2CCC(C)CC2)C=C1 OPNDCHTUSBUNIE-UHFFFAOYSA-N 0.000 description 1
- VUEWBPBFUKIDKK-UHFFFAOYSA-N CC1CCCN(CC2=CC=CC=C2)C1 Chemical compound CC1CCCN(CC2=CC=CC=C2)C1 VUEWBPBFUKIDKK-UHFFFAOYSA-N 0.000 description 1
- RACONJHKSJTVFB-UHFFFAOYSA-N CC1CN(C(=O)C2=CC3=C(C=CC=C3)S2)CCO1 Chemical compound CC1CN(C(=O)C2=CC3=C(C=CC=C3)S2)CCO1 RACONJHKSJTVFB-UHFFFAOYSA-N 0.000 description 1
- VHIFPNISRNUNPF-UHFFFAOYSA-N CC1COCCN(CC2=CC=CC=C2)C1 Chemical compound CC1COCCN(CC2=CC=CC=C2)C1 VHIFPNISRNUNPF-UHFFFAOYSA-N 0.000 description 1
- PCTQYJHEYKPWFL-UHFFFAOYSA-N CC=C1=C2(CCN(C(=O)OC(C)(C)C)CC2)C1 Chemical compound CC=C1=C2(CCN(C(=O)OC(C)(C)C)CC2)C1 PCTQYJHEYKPWFL-UHFFFAOYSA-N 0.000 description 1
- CJJKVFZBANTHKF-UHFFFAOYSA-N CCC1CCCN(C(C2=CC=CC=C2)C2=CC=CC=C2)C1 Chemical compound CCC1CCCN(C(C2=CC=CC=C2)C2=CC=CC=C2)C1 CJJKVFZBANTHKF-UHFFFAOYSA-N 0.000 description 1
- HKERJWCPYOOQID-UHFFFAOYSA-N CCC1CCCN(CC2=CC=CC=C2)CC1 Chemical compound CCC1CCCN(CC2=CC=CC=C2)CC1 HKERJWCPYOOQID-UHFFFAOYSA-N 0.000 description 1
- JTYZOBRFMQUTIH-UHFFFAOYSA-N CCC1CCCN(CC2=CC=NC=C2)C1 Chemical compound CCC1CCCN(CC2=CC=NC=C2)C1 JTYZOBRFMQUTIH-UHFFFAOYSA-N 0.000 description 1
- FTUVTXRVJXOKBX-UHFFFAOYSA-N CCC1CCCN(SO(O)C2=CC=CC3=CC=CN=C32)CC1 Chemical compound CCC1CCCN(SO(O)C2=CC=CC3=CC=CN=C32)CC1 FTUVTXRVJXOKBX-UHFFFAOYSA-N 0.000 description 1
- GFFWHJCYNNHSGO-UHFFFAOYSA-N CCC1CCN(C(=O)C2=CC3=CC=CC=C3C=C2)CCO1 Chemical compound CCC1CCN(C(=O)C2=CC3=CC=CC=C3C=C2)CCO1 GFFWHJCYNNHSGO-UHFFFAOYSA-N 0.000 description 1
- JVPWINYCDYJELL-UHFFFAOYSA-N CCC1CCN(C(=O)C2=CC=CC3=C2C2=C(C=CC=C2)C3=O)CC1 Chemical compound CCC1CCN(C(=O)C2=CC=CC3=C2C2=C(C=CC=C2)C3=O)CC1 JVPWINYCDYJELL-UHFFFAOYSA-N 0.000 description 1
- WOJIOLIUVNJLLC-UHFFFAOYSA-N CCC1CCN(C(=O)C2=CC=CC=C2)CC1 Chemical compound CCC1CCN(C(=O)C2=CC=CC=C2)CC1 WOJIOLIUVNJLLC-UHFFFAOYSA-N 0.000 description 1
- GYJCGHOAEBQEAG-UHFFFAOYSA-N CCC1CCN(C(=O)CC2=CC=CC=C2)CC1 Chemical compound CCC1CCN(C(=O)CC2=CC=CC=C2)CC1 GYJCGHOAEBQEAG-UHFFFAOYSA-N 0.000 description 1
- JHMNYHXNUOBGBU-UHFFFAOYSA-N CCC1CCN(C(=O)N(C2=CC=CC=C2)C2=CC=CC=C2)CC1 Chemical compound CCC1CCN(C(=O)N(C2=CC=CC=C2)C2=CC=CC=C2)CC1 JHMNYHXNUOBGBU-UHFFFAOYSA-N 0.000 description 1
- SPLIRMHEHVPTQH-UHFFFAOYSA-N CCC1CCN(C(C2=CC=CC=C2)(C2=CC=CC=C2)C2=CC=CC=C2)CC1 Chemical compound CCC1CCN(C(C2=CC=CC=C2)(C2=CC=CC=C2)C2=CC=CC=C2)CC1 SPLIRMHEHVPTQH-UHFFFAOYSA-N 0.000 description 1
- VHCZTAUPBZNRBM-UHFFFAOYSA-N CCC1CCN(C(C2=CC=CC=C2)C2=CC=CC=C2)C1 Chemical compound CCC1CCN(C(C2=CC=CC=C2)C2=CC=CC=C2)C1 VHCZTAUPBZNRBM-UHFFFAOYSA-N 0.000 description 1
- CZXVWYLYVPKBAR-UHFFFAOYSA-N CCC1CCN(C)CC1 Chemical compound CCC1CCN(C)CC1 CZXVWYLYVPKBAR-UHFFFAOYSA-N 0.000 description 1
- XPGSXQFWBBPABC-UHFFFAOYSA-N CCC1CCN(CC(C2=CC=CC=C2)C2=CC=CC=C2)CCO1 Chemical compound CCC1CCN(CC(C2=CC=CC=C2)C2=CC=CC=C2)CCO1 XPGSXQFWBBPABC-UHFFFAOYSA-N 0.000 description 1
- YXHCTAAWJMCWCX-UHFFFAOYSA-N CCC1CCN(CC2=C3C=CC=CC3=CC3=CC=CC=C32)CC1 Chemical compound CCC1CCN(CC2=C3C=CC=CC3=CC3=CC=CC=C32)CC1 YXHCTAAWJMCWCX-UHFFFAOYSA-N 0.000 description 1
- VMUOXMZAVAFFRR-UHFFFAOYSA-N CCC1CCN(CC2=CC=CC=C2)C1 Chemical compound CCC1CCN(CC2=CC=CC=C2)C1 VMUOXMZAVAFFRR-UHFFFAOYSA-N 0.000 description 1
- CGXQRTLPIDNJRD-UHFFFAOYSA-N CCC1CCN(CC2CC2)CC1 Chemical compound CCC1CCN(CC2CC2)CC1 CGXQRTLPIDNJRD-UHFFFAOYSA-N 0.000 description 1
- GYIYXAPUMLQTPL-UHFFFAOYSA-N CCC1CCN(SO(C)O)CC1 Chemical compound CCC1CCN(SO(C)O)CC1 GYIYXAPUMLQTPL-UHFFFAOYSA-N 0.000 description 1
- BYUGOBKSTRNKFP-UHFFFAOYSA-N CCC1CCN(SO(O)C2=C(C)C3=C(C=CC(Cl)=C3)S2)CC1 Chemical compound CCC1CCN(SO(O)C2=C(C)C3=C(C=CC(Cl)=C3)S2)CC1 BYUGOBKSTRNKFP-UHFFFAOYSA-N 0.000 description 1
- ADTCISKQFHUFFL-UHFFFAOYSA-N CCC1CCN(SO(O)C2=CC=CC3=CC=CC=C32)CC1 Chemical compound CCC1CCN(SO(O)C2=CC=CC3=CC=CC=C32)CC1 ADTCISKQFHUFFL-UHFFFAOYSA-N 0.000 description 1
- KWHPWBXOLZTZMJ-UHFFFAOYSA-N CCC1CCNCC1 Chemical compound CCC1CCNCC1 KWHPWBXOLZTZMJ-UHFFFAOYSA-N 0.000 description 1
- SGLZILCXJIUJBJ-UHFFFAOYSA-N CCC1CN(P(=O)(C2=CC=CC=C2)C2=CC=CC=C2)CCO1 Chemical compound CCC1CN(P(=O)(C2=CC=CC=C2)C2=CC=CC=C2)CCO1 SGLZILCXJIUJBJ-UHFFFAOYSA-N 0.000 description 1
- NPBBKXBEVQEHKV-UHFFFAOYSA-N CCC1COCCN(CC2=CC=CC=C2)C1 Chemical compound CCC1COCCN(CC2=CC=CC=C2)C1 NPBBKXBEVQEHKV-UHFFFAOYSA-N 0.000 description 1
- JPHXCGWXPOHSMR-UHFFFAOYSA-N CCCC1CCCN(C(=O)C2=CC3=NON=C3C=C2)CC1 Chemical compound CCCC1CCCN(C(=O)C2=CC3=NON=C3C=C2)CC1 JPHXCGWXPOHSMR-UHFFFAOYSA-N 0.000 description 1
- PNFZTKFNBOWQKM-UHFFFAOYSA-N CCCC1CCN(C(C2=CC=CC=C2)C2=CC=CC=C2)CC1 Chemical compound CCCC1CCN(C(C2=CC=CC=C2)C2=CC=CC=C2)CC1 PNFZTKFNBOWQKM-UHFFFAOYSA-N 0.000 description 1
- NCHWIEYRJYYVCL-UHFFFAOYSA-N CCCC1CCN(C2C3=CC=CC=C3C3=C2C=CC=C3)CC1 Chemical compound CCCC1CCN(C2C3=CC=CC=C3C3=C2C=CC=C3)CC1 NCHWIEYRJYYVCL-UHFFFAOYSA-N 0.000 description 1
- NGNKIKXQDNZBFN-UHFFFAOYSA-N CCCC1CN(C(=O)N2CCCC3=C2C=CC=C3)CCO1 Chemical compound CCCC1CN(C(=O)N2CCCC3=C2C=CC=C3)CCO1 NGNKIKXQDNZBFN-UHFFFAOYSA-N 0.000 description 1
- OTFGILQNXYNSIW-UHFFFAOYSA-N CCCC1CN(C(C2=CC=CC=C2)C2=CC=CC=C2)CCO1 Chemical compound CCCC1CN(C(C2=CC=CC=C2)C2=CC=CC=C2)CCO1 OTFGILQNXYNSIW-UHFFFAOYSA-N 0.000 description 1
- FXZCMEOQXSRCGF-UHFFFAOYSA-N CCCC1CN(C2=CC=CC=N2)CCO1 Chemical compound CCCC1CN(C2=CC=CC=N2)CCO1 FXZCMEOQXSRCGF-UHFFFAOYSA-N 0.000 description 1
- YKBHFSWRSVCBCN-UHFFFAOYSA-N CCCC=C1CCN(C(=O)OC(C)(C)C)CC1 Chemical compound CCCC=C1CCN(C(=O)OC(C)(C)C)CC1 YKBHFSWRSVCBCN-UHFFFAOYSA-N 0.000 description 1
- ZGWATEKMPDNQFM-UHFFFAOYSA-N CCCC=C1CCN(C(C2=CC=CC=C2)C2=CC=CC=C2)CC1 Chemical compound CCCC=C1CCN(C(C2=CC=CC=C2)C2=CC=CC=C2)CC1 ZGWATEKMPDNQFM-UHFFFAOYSA-N 0.000 description 1
- REUKRNAMFNVGPA-UHFFFAOYSA-N CCCCC1(O)CCN(C(C2=CC=CC=C2)C2=CC=CC=C2)CC1 Chemical compound CCCCC1(O)CCN(C(C2=CC=CC=C2)C2=CC=CC=C2)CC1 REUKRNAMFNVGPA-UHFFFAOYSA-N 0.000 description 1
- KTLNULDALWGMKW-UHFFFAOYSA-N CCCCC1(O)CCN(CC2=CC=CC=C2)CC1 Chemical compound CCCCC1(O)CCN(CC2=CC=CC=C2)CC1 KTLNULDALWGMKW-UHFFFAOYSA-N 0.000 description 1
- DBNBPNSBAVLAQV-UHFFFAOYSA-N CCCCC1=CCN(C(C2=CC=CC=C2)C2=CC=CC=C2)CC1 Chemical compound CCCCC1=CCN(C(C2=CC=CC=C2)C2=CC=CC=C2)CC1 DBNBPNSBAVLAQV-UHFFFAOYSA-N 0.000 description 1
- VONSPQSYQVOVIB-UHFFFAOYSA-N CCCCC1=CCN(CC2=CC=CC=C2)CC1 Chemical compound CCCCC1=CCN(CC2=CC=CC=C2)CC1 VONSPQSYQVOVIB-UHFFFAOYSA-N 0.000 description 1
- HNTYQPHJOGTNLB-UHFFFAOYSA-N CCCCC1CC2CCC(C1)N2C(C1=CC=CC=C1)C1=CC=CC=C1 Chemical compound CCCCC1CC2CCC(C1)N2C(C1=CC=CC=C1)C1=CC=CC=C1 HNTYQPHJOGTNLB-UHFFFAOYSA-N 0.000 description 1
- FMLQUDFDYZBQPX-UHFFFAOYSA-N CCCCC1CC2CCC(C1)N2CC1=CC=CC=C1 Chemical compound CCCCC1CC2CCC(C1)N2CC1=CC=CC=C1 FMLQUDFDYZBQPX-UHFFFAOYSA-N 0.000 description 1
- UOFQBSGWGKHSAT-UHFFFAOYSA-N CCCCC1CCCN(C(=O)N(CC2=CC=CC=C2)C2=CC=CC=C2)CC1 Chemical compound CCCCC1CCCN(C(=O)N(CC2=CC=CC=C2)C2=CC=CC=C2)CC1 UOFQBSGWGKHSAT-UHFFFAOYSA-N 0.000 description 1
- BGURORPCGSGHHO-UHFFFAOYSA-N CCCCC1CCCN(C2C3=C(C=CC=C3)COC3=C2C=CC=C3)CC1 Chemical compound CCCCC1CCCN(C2C3=C(C=CC=C3)COC3=C2C=CC=C3)CC1 BGURORPCGSGHHO-UHFFFAOYSA-N 0.000 description 1
- YIXPCGTWPXCWBZ-UHFFFAOYSA-N CCCCC1CCN(C(=O)C(=O)C2=CN(C3=CC=CC=C3)C=C2)CC1 Chemical compound CCCCC1CCN(C(=O)C(=O)C2=CN(C3=CC=CC=C3)C=C2)CC1 YIXPCGTWPXCWBZ-UHFFFAOYSA-N 0.000 description 1
- XCQFHBNGJWLDRY-UHFFFAOYSA-N CCCCC1CCN(C(=O)C(C)(C)C)CC1 Chemical compound CCCCC1CCN(C(=O)C(C)(C)C)CC1 XCQFHBNGJWLDRY-UHFFFAOYSA-N 0.000 description 1
- DLYSEMYHIKJAMT-UHFFFAOYSA-N CCCCC1CCN(C(=O)C(C2=CC=CC=C2)C2=CC=CC=C2)C1 Chemical compound CCCCC1CCN(C(=O)C(C2=CC=CC=C2)C2=CC=CC=C2)C1 DLYSEMYHIKJAMT-UHFFFAOYSA-N 0.000 description 1
- CBCLEBOJKZLCPK-UHFFFAOYSA-N CCCCC1CCN(C(=O)C(C2=CC=CC=C2)C2=CC=CC=C2)CC1C Chemical compound CCCCC1CCN(C(=O)C(C2=CC=CC=C2)C2=CC=CC=C2)CC1C CBCLEBOJKZLCPK-UHFFFAOYSA-N 0.000 description 1
- XVJPPTYCGLWLBV-UHFFFAOYSA-N CCCCC1CCN(C(=O)C2=C(Cl)C=CC=C2Cl)CC1 Chemical compound CCCCC1CCN(C(=O)C2=C(Cl)C=CC=C2Cl)CC1 XVJPPTYCGLWLBV-UHFFFAOYSA-N 0.000 description 1
- PSGBHWCUTNGOIJ-UHFFFAOYSA-N CCCCC1CCN(C(=O)C2=CC=CC=C2C(=O)O)CC1 Chemical compound CCCCC1CCN(C(=O)C2=CC=CC=C2C(=O)O)CC1 PSGBHWCUTNGOIJ-UHFFFAOYSA-N 0.000 description 1
- ZSMARNYPLDLJTC-UHFFFAOYSA-N CCCCC1CCN(C(=O)C2=CC=CO2)CC1 Chemical compound CCCCC1CCN(C(=O)C2=CC=CO2)CC1 ZSMARNYPLDLJTC-UHFFFAOYSA-N 0.000 description 1
- YDRWIYZFFJSAIV-UHFFFAOYSA-N CCCCC1CCN(C(=O)N(C(C)C)C(C)C)CC1 Chemical compound CCCCC1CCN(C(=O)N(C(C)C)C(C)C)CC1 YDRWIYZFFJSAIV-UHFFFAOYSA-N 0.000 description 1
- PSDXXIVSQJMLNO-UHFFFAOYSA-N CCCCC1CCN(C(=O)N(C)C)CC1 Chemical compound CCCCC1CCN(C(=O)N(C)C)CC1 PSDXXIVSQJMLNO-UHFFFAOYSA-N 0.000 description 1
- NVGAHQVTYQREQS-UHFFFAOYSA-N CCCCC1CCN(C(=O)N(CC2=CC=CC=C2)CC2=CC=CC=C2)CC1 Chemical compound CCCCC1CCN(C(=O)N(CC2=CC=CC=C2)CC2=CC=CC=C2)CC1 NVGAHQVTYQREQS-UHFFFAOYSA-N 0.000 description 1
- NHDWDHLGYKTUAL-UHFFFAOYSA-N CCCCC1CCN(C(=O)NCC2=CC=CO2)CC1 Chemical compound CCCCC1CCN(C(=O)NCC2=CC=CO2)CC1 NHDWDHLGYKTUAL-UHFFFAOYSA-N 0.000 description 1
- ISRXOZVQPXGNGZ-UHFFFAOYSA-N CCCCC1CCN(C(=O)OCC2=CC=CC=C2)CC1 Chemical compound CCCCC1CCN(C(=O)OCC2=CC=CC=C2)CC1 ISRXOZVQPXGNGZ-UHFFFAOYSA-N 0.000 description 1
- LHOMVJLCTJPHPP-UHFFFAOYSA-N CCCCC1CCN(C(C)C)CC1 Chemical compound CCCCC1CCN(C(C)C)CC1 LHOMVJLCTJPHPP-UHFFFAOYSA-N 0.000 description 1
- TYKPMHVFGZAPQY-UHFFFAOYSA-N CCCCC1CCN(C(C2=CC=C(F)C=C2)C2=CC=C(F)C=C2)CC1 Chemical compound CCCCC1CCN(C(C2=CC=C(F)C=C2)C2=CC=C(F)C=C2)CC1 TYKPMHVFGZAPQY-UHFFFAOYSA-N 0.000 description 1
- ZGXYXSXWOKGDTB-UHFFFAOYSA-N CCCCC1CCN(C(C2=CC=CC=C2)(C2=CC=CC=C2)C2=CC=CC=C2)CC1 Chemical compound CCCCC1CCN(C(C2=CC=CC=C2)(C2=CC=CC=C2)C2=CC=CC=C2)CC1 ZGXYXSXWOKGDTB-UHFFFAOYSA-N 0.000 description 1
- AOWYOLSJYFNXSY-UHFFFAOYSA-N CCCCC1CCN(C(C2=CC=CC=C2)C2=CC=C(O)C=C2)CC1 Chemical compound CCCCC1CCN(C(C2=CC=CC=C2)C2=CC=C(O)C=C2)CC1 AOWYOLSJYFNXSY-UHFFFAOYSA-N 0.000 description 1
- HQDLNIIHXLKTIE-UHFFFAOYSA-N CCCCC1CCN(C(C2=CC=CC=C2)C2=CC=C(OC)C=C2)CC1 Chemical compound CCCCC1CCN(C(C2=CC=CC=C2)C2=CC=C(OC)C=C2)CC1 HQDLNIIHXLKTIE-UHFFFAOYSA-N 0.000 description 1
- LIFCTHFMMMELCQ-UHFFFAOYSA-N CCCCC1CCN(C(C2=CC=CC=C2)C2=CC=CC=C2)C(=O)C1 Chemical compound CCCCC1CCN(C(C2=CC=CC=C2)C2=CC=CC=C2)C(=O)C1 LIFCTHFMMMELCQ-UHFFFAOYSA-N 0.000 description 1
- OTRMZRWHWHDTIF-UHFFFAOYSA-N CCCCC1CCN(C(C2=CC=CC=C2)C2=CC=CC=C2)C1 Chemical compound CCCCC1CCN(C(C2=CC=CC=C2)C2=CC=CC=C2)C1 OTRMZRWHWHDTIF-UHFFFAOYSA-N 0.000 description 1
- IQXANLLUJMSJPT-UHFFFAOYSA-N CCCCC1CCN(C(C2=CC=CC=C2)C2=CC=CC=C2)CC1C Chemical compound CCCCC1CCN(C(C2=CC=CC=C2)C2=CC=CC=C2)CC1C IQXANLLUJMSJPT-UHFFFAOYSA-N 0.000 description 1
- PITZOUMFPXAFJL-UHFFFAOYSA-N CCCCC1CCN(C(C2=CC=CC=C2)C2=CC=CS2)CC1 Chemical compound CCCCC1CCN(C(C2=CC=CC=C2)C2=CC=CS2)CC1 PITZOUMFPXAFJL-UHFFFAOYSA-N 0.000 description 1
- QCIXDJMAUNDTIB-UHFFFAOYSA-N CCCCC1CCN(C(C2=CC=CC=C2)C2=CC=NC=C2)CC1 Chemical compound CCCCC1CCN(C(C2=CC=CC=C2)C2=CC=NC=C2)CC1 QCIXDJMAUNDTIB-UHFFFAOYSA-N 0.000 description 1
- HYORBQWFORKMAC-UHFFFAOYSA-N CCCCC1CCN(C(C2=CC=CC=C2)C2=CN=CC=C2)CC1 Chemical compound CCCCC1CCN(C(C2=CC=CC=C2)C2=CN=CC=C2)CC1 HYORBQWFORKMAC-UHFFFAOYSA-N 0.000 description 1
- LNVPORUWCYYASP-UHFFFAOYSA-N CCCCC1CCN(C(C2=CC=CC=C2)C2CCCCC2)CC1 Chemical compound CCCCC1CCN(C(C2=CC=CC=C2)C2CCCCC2)CC1 LNVPORUWCYYASP-UHFFFAOYSA-N 0.000 description 1
- UAURFPDPYXFVRC-UHFFFAOYSA-N CCCCC1CCN(C2C3=C(C=CC=C3)CSC3=C2C=CS3)CC1 Chemical compound CCCCC1CCN(C2C3=C(C=CC=C3)CSC3=C2C=CS3)CC1 UAURFPDPYXFVRC-UHFFFAOYSA-N 0.000 description 1
- YNMSNGMPXDAWPM-UHFFFAOYSA-N CCCCC1CCN(C2C3=C(C=CC=C3)OC3=C2C=CC=N3)CC1 Chemical compound CCCCC1CCN(C2C3=C(C=CC=C3)OC3=C2C=CC=N3)CC1 YNMSNGMPXDAWPM-UHFFFAOYSA-N 0.000 description 1
- YMMKUFAKKIUYIL-UHFFFAOYSA-N CCCCC1CCN(C2CC2)CC1 Chemical compound CCCCC1CCN(C2CC2)CC1 YMMKUFAKKIUYIL-UHFFFAOYSA-N 0.000 description 1
- BBUWQAXBXZJTHN-UHFFFAOYSA-N CCCCC1CCN(CC2=CC3=CC=CC=C3C=C2)C1 Chemical compound CCCCC1CCN(CC2=CC3=CC=CC=C3C=C2)C1 BBUWQAXBXZJTHN-UHFFFAOYSA-N 0.000 description 1
- JHSITHUJQHUHNL-UHFFFAOYSA-N CCCCC1CCN(CC2=CC3=NON=C3C=C2)CC1 Chemical compound CCCCC1CCN(CC2=CC3=NON=C3C=C2)CC1 JHSITHUJQHUHNL-UHFFFAOYSA-N 0.000 description 1
- CSUDVIZGNHFOQI-UHFFFAOYSA-N CCCCC1CCN(CC2=CC=C(C3=CC=CC=C3)C=C2)CC1 Chemical compound CCCCC1CCN(CC2=CC=C(C3=CC=CC=C3)C=C2)CC1 CSUDVIZGNHFOQI-UHFFFAOYSA-N 0.000 description 1
- UTMDSVVWZHJXLM-UHFFFAOYSA-N CCCCC1CCN(CC2=CC=C(O)C=C2)CC1 Chemical compound CCCCC1CCN(CC2=CC=C(O)C=C2)CC1 UTMDSVVWZHJXLM-UHFFFAOYSA-N 0.000 description 1
- HOWMHWKVSKBGGM-UHFFFAOYSA-N CCCCC1CCN(CC2=CC=C(OC)C=C2)CC1 Chemical compound CCCCC1CCN(CC2=CC=C(OC)C=C2)CC1 HOWMHWKVSKBGGM-UHFFFAOYSA-N 0.000 description 1
- LQADSUHWHYJULH-UHFFFAOYSA-N CCCCC1CCN(CC2=CC=CC=C2)C(=O)C1 Chemical compound CCCCC1CCN(CC2=CC=CC=C2)C(=O)C1 LQADSUHWHYJULH-UHFFFAOYSA-N 0.000 description 1
- XQLLOZXNRILLKR-UHFFFAOYSA-N CCCCC1CCN(CC2=CC=CC=C2)C1 Chemical compound CCCCC1CCN(CC2=CC=CC=C2)C1 XQLLOZXNRILLKR-UHFFFAOYSA-N 0.000 description 1
- WTBWQDWWNRBPES-UHFFFAOYSA-N CCCCC1CCN(CC2=CC=CC=C2)CC1C Chemical compound CCCCC1CCN(CC2=CC=CC=C2)CC1C WTBWQDWWNRBPES-UHFFFAOYSA-N 0.000 description 1
- KOAOJRSXOVQHIK-UHFFFAOYSA-N CCCCC1CCN(CC2=CC=CN=C2)CC1 Chemical compound CCCCC1CCN(CC2=CC=CN=C2)CC1 KOAOJRSXOVQHIK-UHFFFAOYSA-N 0.000 description 1
- ZLZUHEKBUNTBDL-UHFFFAOYSA-N CCCCC1CCN(CC2CCCNC2)CC1 Chemical compound CCCCC1CCN(CC2CCCNC2)CC1 ZLZUHEKBUNTBDL-UHFFFAOYSA-N 0.000 description 1
- XJEATNRKNOGKCL-UHFFFAOYSA-N CCCCC1CCN(CCC2CCNCC2)CC1 Chemical compound CCCCC1CCN(CCC2CCNCC2)CC1 XJEATNRKNOGKCL-UHFFFAOYSA-N 0.000 description 1
- ZUAWNRIWUJBURF-UHFFFAOYSA-N CCCCC1CCN(CCN2CCCCC2)CC1 Chemical compound CCCCC1CCN(CCN2CCCCC2)CC1 ZUAWNRIWUJBURF-UHFFFAOYSA-N 0.000 description 1
- UIWAWNDYXJLGGK-UHFFFAOYSA-N CCCCC1CCN(SO(O)C2=CC=CC3=C2N=CC=C3)CC1 Chemical compound CCCCC1CCN(SO(O)C2=CC=CC3=C2N=CC=C3)CC1 UIWAWNDYXJLGGK-UHFFFAOYSA-N 0.000 description 1
- RFNNXNFZHAADRP-UHFFFAOYSA-N CCCCC1CCN(SO(O)C2=CC=CC3=CC=CC=C32)CC1 Chemical compound CCCCC1CCN(SO(O)C2=CC=CC3=CC=CC=C32)CC1 RFNNXNFZHAADRP-UHFFFAOYSA-N 0.000 description 1
- IINRBKYXQJHWLE-UHFFFAOYSA-N CCCCC1CCN(SO(O)C2=CC=CC3=NON=C23)CC1 Chemical compound CCCCC1CCN(SO(O)C2=CC=CC3=NON=C23)CC1 IINRBKYXQJHWLE-UHFFFAOYSA-N 0.000 description 1
- OHTHRLKNGAGZQN-UHFFFAOYSA-N CCCCC1CN(C(=O)C(C2=CC=CC=C2)C2=CC=CC=C2)CCO1 Chemical compound CCCCC1CN(C(=O)C(C2=CC=CC=C2)C2=CC=CC=C2)CCO1 OHTHRLKNGAGZQN-UHFFFAOYSA-N 0.000 description 1
- AGKMRHJCIBZGFM-UHFFFAOYSA-N CCCCC1CN(C(=O)C2=CC=CC=C2)C1 Chemical compound CCCCC1CN(C(=O)C2=CC=CC=C2)C1 AGKMRHJCIBZGFM-UHFFFAOYSA-N 0.000 description 1
- VTHYMEXPUGKAGT-UHFFFAOYSA-N CCCCC1CN(C(C2=CC=CC=C2)C2=CC=CC=C2)C1 Chemical compound CCCCC1CN(C(C2=CC=CC=C2)C2=CC=CC=C2)C1 VTHYMEXPUGKAGT-UHFFFAOYSA-N 0.000 description 1
- UCDLFENPNXDJEF-UHFFFAOYSA-N CCCCCC1CCCN(C(C2=CC=CC=C2)C2=CC=CC=C2)CC1 Chemical compound CCCCCC1CCCN(C(C2=CC=CC=C2)C2=CC=CC=C2)CC1 UCDLFENPNXDJEF-UHFFFAOYSA-N 0.000 description 1
- JBTPHWOCBONPHY-UHFFFAOYSA-N CCCCCC1CCN(C(C)=O)CC1 Chemical compound CCCCCC1CCN(C(C)=O)CC1 JBTPHWOCBONPHY-UHFFFAOYSA-N 0.000 description 1
- FTUOKCDBWHMBRX-UHFFFAOYSA-N CCCCCC1CCN(C(C2=CC=CC=C2)C2=CC=CC=C2)CC1 Chemical compound CCCCCC1CCN(C(C2=CC=CC=C2)C2=CC=CC=C2)CC1 FTUOKCDBWHMBRX-UHFFFAOYSA-N 0.000 description 1
- LUSRWMZNFQSUSP-UHFFFAOYSA-N CCCCCC1CCN(C2C3=C(C=CC=C3)CCC3=C2C=CC=C3)CC1 Chemical compound CCCCCC1CCN(C2C3=C(C=CC=C3)CCC3=C2C=CC=C3)CC1 LUSRWMZNFQSUSP-UHFFFAOYSA-N 0.000 description 1
- WXFBLAOCTZJRMW-UHFFFAOYSA-N CCCCCC1CCN(P(=O)(C2=CC=CC=C2)C2=CC=CC=C2)CC1 Chemical compound CCCCCC1CCN(P(=O)(C2=CC=CC=C2)C2=CC=CC=C2)CC1 WXFBLAOCTZJRMW-UHFFFAOYSA-N 0.000 description 1
- IRDMFABZAYBTMV-UHFFFAOYSA-N CCCCCC1CCN(SO(O)C2=CC3=CC=CC=C3C=C2)CC1 Chemical compound CCCCCC1CCN(SO(O)C2=CC3=CC=CC=C3C=C2)CC1 IRDMFABZAYBTMV-UHFFFAOYSA-N 0.000 description 1
- SZNNNXNOTNMOSK-UHFFFAOYSA-N CCCCCCC1CCN(C(C2=CC=CC=C2)C2=CC=CC=C2)CC1 Chemical compound CCCCCCC1CCN(C(C2=CC=CC=C2)C2=CC=CC=C2)CC1 SZNNNXNOTNMOSK-UHFFFAOYSA-N 0.000 description 1
- XUICYKSNASMRCM-UHFFFAOYSA-N CCCCCCC1CCN(SO(C)O)CC1 Chemical compound CCCCCCC1CCN(SO(C)O)CC1 XUICYKSNASMRCM-UHFFFAOYSA-N 0.000 description 1
- GVMFCPOAYNENIB-UHFFFAOYSA-N CCCCCCC1CCNCC1 Chemical compound CCCCCCC1CCNCC1 GVMFCPOAYNENIB-UHFFFAOYSA-N 0.000 description 1
- KIUWJJMTPLLQPY-UHFFFAOYSA-N CCCCCCCC1CCN(C(C2=CC=CC=C2)C2=CC=CC=C2)CC1 Chemical compound CCCCCCCC1CCN(C(C2=CC=CC=C2)C2=CC=CC=C2)CC1 KIUWJJMTPLLQPY-UHFFFAOYSA-N 0.000 description 1
- LGQCRISGVYTKAH-UHFFFAOYSA-N CCCCCCCCC1CCN(C(=O)C2=CC=CC3=C2C2=C(C=CC=C2)C3=O)CC1 Chemical compound CCCCCCCCC1CCN(C(=O)C2=CC=CC3=C2C2=C(C=CC=C2)C3=O)CC1 LGQCRISGVYTKAH-UHFFFAOYSA-N 0.000 description 1
- KWHDDHWXNGJONB-UHFFFAOYSA-N CCCCCCCCC1CCN(C(=O)C2=CC=CC3=CC=CC=C32)CC1 Chemical compound CCCCCCCCC1CCN(C(=O)C2=CC=CC3=CC=CC=C32)CC1 KWHDDHWXNGJONB-UHFFFAOYSA-N 0.000 description 1
- HPEUHOOGUMHCTB-UHFFFAOYSA-N CCCCCCCCC1CCN(C(C2=CC=CC=C2)C2=CC=CC=C2)CC1 Chemical compound CCCCCCCCC1CCN(C(C2=CC=CC=C2)C2=CC=CC=C2)CC1 HPEUHOOGUMHCTB-UHFFFAOYSA-N 0.000 description 1
- CZRWFIFMYBEXPR-UHFFFAOYSA-N CCCCCCCCC1CCN(CC2CC2)CC1 Chemical compound CCCCCCCCC1CCN(CC2CC2)CC1 CZRWFIFMYBEXPR-UHFFFAOYSA-N 0.000 description 1
- DNWNAXNGQVQUAZ-UHFFFAOYSA-N CCCCCCCCC1CCN(SO(O)C2=CC=CS2)CC1 Chemical compound CCCCCCCCC1CCN(SO(O)C2=CC=CS2)CC1 DNWNAXNGQVQUAZ-UHFFFAOYSA-N 0.000 description 1
- BYDZXCXMJWPTLL-UHFFFAOYSA-N CCCNC1CCN(SO(C)O)CC1 Chemical compound CCCNC1CCN(SO(C)O)CC1 BYDZXCXMJWPTLL-UHFFFAOYSA-N 0.000 description 1
- HEYWHUAQHZJNSZ-UHFFFAOYSA-N CCCNCC(=O)C1CCCN(C(C2=CC=CC=C2)C2=CC=CC=C2)C1 Chemical compound CCCNCC(=O)C1CCCN(C(C2=CC=CC=C2)C2=CC=CC=C2)C1 HEYWHUAQHZJNSZ-UHFFFAOYSA-N 0.000 description 1
- VOXHGPJSJWOFQC-UHFFFAOYSA-N CCCOC1CCCN(C(=O)CC2=CC(F)=CC(F)=C2)CC1 Chemical compound CCCOC1CCCN(C(=O)CC2=CC(F)=CC(F)=C2)CC1 VOXHGPJSJWOFQC-UHFFFAOYSA-N 0.000 description 1
- PUWXHWLBQUJPBT-UHFFFAOYSA-N CCCOC1CCN(CC2CCCCC2)CC1 Chemical compound CCCOC1CCN(CC2CCCCC2)CC1 PUWXHWLBQUJPBT-UHFFFAOYSA-N 0.000 description 1
- GFGWAOBINUTKLY-UHFFFAOYSA-N CCCOCC1CCN(C(=O)NC2=CC=CC3=CC=CC=C32)CC1 Chemical compound CCCOCC1CCN(C(=O)NC2=CC=CC3=CC=CC=C32)CC1 GFGWAOBINUTKLY-UHFFFAOYSA-N 0.000 description 1
- JOXRGBWBLOZBNW-UHFFFAOYSA-N CCCOCCC1CCN(C(C2=CC=CC=C2)C2=CC=CC=C2)CC1 Chemical compound CCCOCCC1CCN(C(C2=CC=CC=C2)C2=CC=CC=C2)CC1 JOXRGBWBLOZBNW-UHFFFAOYSA-N 0.000 description 1
- INLMPVJMGVUMRW-UHFFFAOYSA-N CCN(C)C(=O)C1CCN(C(=O)C2=CC=CC=C2)CC1 Chemical compound CCN(C)C(=O)C1CCN(C(=O)C2=CC=CC=C2)CC1 INLMPVJMGVUMRW-UHFFFAOYSA-N 0.000 description 1
- VQUNGSGMUJKJJG-UHFFFAOYSA-N CCNC(=O)C1CCN(C(C2=CC=CC=C2)C2=CC=CC=C2)CC1 Chemical compound CCNC(=O)C1CCN(C(C2=CC=CC=C2)C2=CC=CC=C2)CC1 VQUNGSGMUJKJJG-UHFFFAOYSA-N 0.000 description 1
- MPPYKPQMMIQDPM-UHFFFAOYSA-N CCNC(=O)OC1CCN(C(C2=CC=CC=C2)C2=CC=CC=C2)CC1 Chemical compound CCNC(=O)OC1CCN(C(C2=CC=CC=C2)C2=CC=CC=C2)CC1 MPPYKPQMMIQDPM-UHFFFAOYSA-N 0.000 description 1
- GMIICJPNVILLFK-UHFFFAOYSA-N CCNC(=O)OC1CCN(CC2=CC=CC=C2)C1 Chemical compound CCNC(=O)OC1CCN(CC2=CC=CC=C2)C1 GMIICJPNVILLFK-UHFFFAOYSA-N 0.000 description 1
- YAMNFYBTMVKZCI-UHFFFAOYSA-N CCNC1CCCN(C(=O)OC(C)(C)C)CC1 Chemical compound CCNC1CCCN(C(=O)OC(C)(C)C)CC1 YAMNFYBTMVKZCI-UHFFFAOYSA-N 0.000 description 1
- QVUDSCSAEQAQNN-UHFFFAOYSA-N CNCC(=O)OC1CCN(C(C2=CC=CC=C2)C2=CC=CC=C2)CC1 Chemical compound CNCC(=O)OC1CCN(C(C2=CC=CC=C2)C2=CC=CC=C2)CC1 QVUDSCSAEQAQNN-UHFFFAOYSA-N 0.000 description 1
- XKNQQSRIJDKVOG-UHFFFAOYSA-N CNCC(=O)OC1CCN(C2CCCCC2)CC1 Chemical compound CNCC(=O)OC1CCN(C2CCCCC2)CC1 XKNQQSRIJDKVOG-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 201000009030 Carcinoma Diseases 0.000 description 1
- 208000017897 Carcinoma of esophagus Diseases 0.000 description 1
- DLGOEMSEDOSKAD-UHFFFAOYSA-N Carmustine Chemical compound ClCCNC(=O)N(N=O)CCCl DLGOEMSEDOSKAD-UHFFFAOYSA-N 0.000 description 1
- 244000060011 Cocos nucifera Species 0.000 description 1
- 235000013162 Cocos nucifera Nutrition 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 244000303965 Cyamopsis psoralioides Species 0.000 description 1
- 229920000858 Cyclodextrin Polymers 0.000 description 1
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 1
- 229930105110 Cyclosporin A Natural products 0.000 description 1
- PMATZTZNYRCHOR-CGLBZJNRSA-N Cyclosporin A Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 description 1
- 108010036949 Cyclosporine Proteins 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
- RGHNJXZEOKUKBD-SQOUGZDYSA-M D-gluconate Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O RGHNJXZEOKUKBD-SQOUGZDYSA-M 0.000 description 1
- 108010092160 Dactinomycin Proteins 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 235000019739 Dicalciumphosphate Nutrition 0.000 description 1
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 description 1
- 208000009849 Female Genital Neoplasms Diseases 0.000 description 1
- 229920001917 Ficoll Polymers 0.000 description 1
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 1
- 229930091371 Fructose Natural products 0.000 description 1
- 239000005715 Fructose Substances 0.000 description 1
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 description 1
- 102000005720 Glutathione transferase Human genes 0.000 description 1
- 108010070675 Glutathione transferase Proteins 0.000 description 1
- BLCLNMBMMGCOAS-URPVMXJPSA-N Goserelin Chemical compound C([C@@H](C(=O)N[C@H](COC(C)(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N1[C@@H](CCC1)C(=O)NNC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H]1NC(=O)CC1)C1=CC=C(O)C=C1 BLCLNMBMMGCOAS-URPVMXJPSA-N 0.000 description 1
- 108010069236 Goserelin Proteins 0.000 description 1
- 206010019695 Hepatic neoplasm Diseases 0.000 description 1
- 208000017604 Hodgkin disease Diseases 0.000 description 1
- 208000010747 Hodgkins lymphoma Diseases 0.000 description 1
- 108091006905 Human Serum Albumin Proteins 0.000 description 1
- 102000008100 Human Serum Albumin Human genes 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- VSNHCAURESNICA-UHFFFAOYSA-N Hydroxyurea Chemical compound NC(=O)NO VSNHCAURESNICA-UHFFFAOYSA-N 0.000 description 1
- 206010020651 Hyperkinesia Diseases 0.000 description 1
- 208000000269 Hyperkinesis Diseases 0.000 description 1
- 206010020843 Hyperthermia Diseases 0.000 description 1
- 208000008839 Kidney Neoplasms Diseases 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
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- 239000005639 Lauric acid Substances 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 206010026749 Mania Diseases 0.000 description 1
- 238000003820 Medium-pressure liquid chromatography Methods 0.000 description 1
- 108010047230 Member 1 Subfamily B ATP Binding Cassette Transporter Proteins 0.000 description 1
- 102000003792 Metallothionein Human genes 0.000 description 1
- 108090000157 Metallothionein Proteins 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 description 1
- 102000009493 Neurokinin receptors Human genes 0.000 description 1
- 108050000302 Neurokinin receptors Proteins 0.000 description 1
- GQLSXYZTSHHXOG-WUKNDPDISA-N O=C(/C=C/C1=C[N+]([O-])=CC=C1)NCCCCC1CCN(C(C2=CC=CC=C2)C2=CC=CC=C2)CC1 Chemical compound O=C(/C=C/C1=C[N+]([O-])=CC=C1)NCCCCC1CCN(C(C2=CC=CC=C2)C2=CC=CC=C2)CC1 GQLSXYZTSHHXOG-WUKNDPDISA-N 0.000 description 1
- QMCHNGAUKGVBGH-UHFFFAOYSA-N OCCCCC1CCN(C(C2=CC=CC=C2)C2=CC=CC=C2)CC1 Chemical compound OCCCCC1CCN(C(C2=CC=CC=C2)C2=CC=CC=C2)CC1 QMCHNGAUKGVBGH-UHFFFAOYSA-N 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 229930012538 Paclitaxel Natural products 0.000 description 1
- 239000005662 Paraffin oil Substances 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 229920000954 Polyglycolide Polymers 0.000 description 1
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 102100024304 Protachykinin-1 Human genes 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- 206010038389 Renal cancer Diseases 0.000 description 1
- 206010039491 Sarcoma Diseases 0.000 description 1
- 206010039966 Senile dementia Diseases 0.000 description 1
- 208000000453 Skin Neoplasms Diseases 0.000 description 1
- 231100000632 Spindle poison Toxicity 0.000 description 1
- 208000005718 Stomach Neoplasms Diseases 0.000 description 1
- 101800003906 Substance P Proteins 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- QJJXYPPXXYFBGM-LFZNUXCKSA-N Tacrolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1\C=C(/C)[C@@H]1[C@H](C)[C@@H](O)CC(=O)[C@H](CC=C)/C=C(C)/C[C@H](C)C[C@H](OC)[C@H]([C@H](C[C@H]2C)OC)O[C@@]2(O)C(=O)C(=O)N2CCCC[C@H]2C(=O)O1 QJJXYPPXXYFBGM-LFZNUXCKSA-N 0.000 description 1
- GUGOEEXESWIERI-UHFFFAOYSA-N Terfenadine Chemical compound C1=CC(C(C)(C)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 GUGOEEXESWIERI-UHFFFAOYSA-N 0.000 description 1
- FOCVUCIESVLUNU-UHFFFAOYSA-N Thiotepa Chemical compound C1CN1P(N1CC1)(=S)N1CC1 FOCVUCIESVLUNU-UHFFFAOYSA-N 0.000 description 1
- 208000024770 Thyroid neoplasm Diseases 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 240000008042 Zea mays Species 0.000 description 1
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 1
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 1
- VOWMRECKIQVVPP-UHFFFAOYSA-N [H]N1CCC(OCCC)CC1 Chemical compound [H]N1CCC(OCCC)CC1 VOWMRECKIQVVPP-UHFFFAOYSA-N 0.000 description 1
- QPQGTZMAQRXCJW-UHFFFAOYSA-N [chloro(phenyl)phosphoryl]benzene Chemical compound C=1C=CC=CC=1P(=O)(Cl)C1=CC=CC=C1 QPQGTZMAQRXCJW-UHFFFAOYSA-N 0.000 description 1
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 1
- FKCBLVCOSCZFHV-UHFFFAOYSA-N acetonitrile;ethanol Chemical compound CCO.CC#N FKCBLVCOSCZFHV-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000001252 acrylic acid derivatives Chemical class 0.000 description 1
- RJURFGZVJUQBHK-IIXSONLDSA-N actinomycin D Chemical compound C[C@H]1OC(=O)[C@H](C(C)C)N(C)C(=O)CN(C)C(=O)[C@@H]2CCCN2C(=O)[C@@H](C(C)C)NC(=O)[C@H]1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)N[C@@H]4C(=O)N[C@@H](C(N5CCC[C@H]5C(=O)N(C)CC(=O)N(C)[C@@H](C(C)C)C(=O)O[C@@H]4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-IIXSONLDSA-N 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- WNLRTRBMVRJNCN-UHFFFAOYSA-N adipic acid Chemical class OC(=O)CCCCC(O)=O WNLRTRBMVRJNCN-UHFFFAOYSA-N 0.000 description 1
- 208000024447 adrenal gland neoplasm Diseases 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- WNROFYMDJYEPJX-UHFFFAOYSA-K aluminium hydroxide Chemical class [OH-].[OH-].[OH-].[Al+3] WNROFYMDJYEPJX-UHFFFAOYSA-K 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
- 235000001014 amino acid Nutrition 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 125000000129 anionic group Chemical group 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 230000003288 anthiarrhythmic effect Effects 0.000 description 1
- 230000001387 anti-histamine Effects 0.000 description 1
- 230000000340 anti-metabolite Effects 0.000 description 1
- 230000000118 anti-neoplastic effect Effects 0.000 description 1
- 239000000739 antihistaminic agent Substances 0.000 description 1
- 229940100197 antimetabolite Drugs 0.000 description 1
- 239000002256 antimetabolite Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 239000008122 artificial sweetener Substances 0.000 description 1
- 239000012752 auxiliary agent Substances 0.000 description 1
- VSRXQHXAPYXROS-UHFFFAOYSA-N azanide;cyclobutane-1,1-dicarboxylic acid;platinum(2+) Chemical compound [NH2-].[NH2-].[Pt+2].OC(=O)C1(C(O)=O)CCC1 VSRXQHXAPYXROS-UHFFFAOYSA-N 0.000 description 1
- PCCNIENXBRUYFK-UHFFFAOYSA-O azanium;cerium(4+);pentanitrate Chemical compound [NH4+].[Ce+4].[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O PCCNIENXBRUYFK-UHFFFAOYSA-O 0.000 description 1
- 229960002170 azathioprine Drugs 0.000 description 1
- LMEKQMALGUDUQG-UHFFFAOYSA-N azathioprine Chemical compound CN1C=NC([N+]([O-])=O)=C1SC1=NC=NC2=C1NC=N2 LMEKQMALGUDUQG-UHFFFAOYSA-N 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 206010061691 benign mesothelioma Diseases 0.000 description 1
- 235000012216 bentonite Nutrition 0.000 description 1
- 125000004604 benzisothiazolyl group Chemical group S1N=C(C2=C1C=CC=C2)* 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- UDEWPOVQBGFNGE-UHFFFAOYSA-N benzoic acid n-propyl ester Natural products CCCOC(=O)C1=CC=CC=C1 UDEWPOVQBGFNGE-UHFFFAOYSA-N 0.000 description 1
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 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
- 239000011230 binding agent Substances 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
- 210000000601 blood cell Anatomy 0.000 description 1
- 210000001124 body fluid Anatomy 0.000 description 1
- 239000010839 body fluid Substances 0.000 description 1
- 206010006007 bone sarcoma Diseases 0.000 description 1
- OQROAIRCEOBYJA-UHFFFAOYSA-N bromodiphenylmethane Chemical compound C=1C=CC=CC=1C(Br)C1=CC=CC=C1 OQROAIRCEOBYJA-UHFFFAOYSA-N 0.000 description 1
- 210000000621 bronchi Anatomy 0.000 description 1
- 208000003362 bronchogenic carcinoma Diseases 0.000 description 1
- 239000013590 bulk material Substances 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 229960002092 busulfan Drugs 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 125000005521 carbonamide group Chemical group 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-N carbonic acid monoamide Natural products NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 description 1
- 229960004562 carboplatin Drugs 0.000 description 1
- 229960005243 carmustine Drugs 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000007910 chewable tablet Substances 0.000 description 1
- 239000000544 cholinesterase inhibitor Substances 0.000 description 1
- 208000024207 chronic leukemia Diseases 0.000 description 1
- 229960001265 ciclosporin Drugs 0.000 description 1
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 1
- 229960004316 cisplatin Drugs 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 239000010941 cobalt Substances 0.000 description 1
- 229910017052 cobalt Inorganic materials 0.000 description 1
- GUTLYIVDDKVIGB-UHFFFAOYSA-N cobalt atom Chemical compound [Co] GUTLYIVDDKVIGB-UHFFFAOYSA-N 0.000 description 1
- 239000003240 coconut oil Substances 0.000 description 1
- 235000019864 coconut oil Nutrition 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000009109 curative therapy Methods 0.000 description 1
- 125000005366 cycloalkylthio group Chemical group 0.000 description 1
- 229940097362 cyclodextrins Drugs 0.000 description 1
- 229960004397 cyclophosphamide Drugs 0.000 description 1
- 229960000684 cytarabine Drugs 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 238000002784 cytotoxicity assay Methods 0.000 description 1
- 231100000263 cytotoxicity test Toxicity 0.000 description 1
- 229960003901 dacarbazine Drugs 0.000 description 1
- 229960000640 dactinomycin Drugs 0.000 description 1
- STQGQHZAVUOBTE-VGBVRHCVSA-N daunorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(C)=O)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 STQGQHZAVUOBTE-VGBVRHCVSA-N 0.000 description 1
- 229960000975 daunorubicin Drugs 0.000 description 1
- 239000003405 delayed action preparation Substances 0.000 description 1
- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 description 1
- 229940038472 dicalcium phosphate Drugs 0.000 description 1
- 229910000390 dicalcium phosphate Inorganic materials 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 238000009792 diffusion process Methods 0.000 description 1
- 125000004925 dihydropyridyl group Chemical group N1(CC=CC=C1)* 0.000 description 1
- 230000003292 diminished effect Effects 0.000 description 1
- MPFLRYZEEAQMLQ-UHFFFAOYSA-N dinicotinic acid Chemical class OC(=O)C1=CN=CC(C(O)=O)=C1 MPFLRYZEEAQMLQ-UHFFFAOYSA-N 0.000 description 1
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 235000021186 dishes Nutrition 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000003534 dna topoisomerase inhibitor Substances 0.000 description 1
- 229960004679 doxorubicin Drugs 0.000 description 1
- 238000007877 drug screening Methods 0.000 description 1
- JROGBPMEKVAPEH-GXGBFOEMSA-N emetine dihydrochloride Chemical compound Cl.Cl.N1CCC2=CC(OC)=C(OC)C=C2[C@H]1C[C@H]1C[C@H]2C3=CC(OC)=C(OC)C=C3CCN2C[C@@H]1CC JROGBPMEKVAPEH-GXGBFOEMSA-N 0.000 description 1
- 238000004945 emulsification Methods 0.000 description 1
- 238000005538 encapsulation Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000003628 erosive effect Effects 0.000 description 1
- PSLIMVZEAPALCD-UHFFFAOYSA-N ethanol;ethoxyethane Chemical compound CCO.CCOCC PSLIMVZEAPALCD-UHFFFAOYSA-N 0.000 description 1
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 1
- KMTDQMXKXXDKNT-UHFFFAOYSA-N ethyl 1-benzhydrylpiperidine-3-carboxylate Chemical compound C1C(C(=O)OCC)CCCN1C(C=1C=CC=CC=1)C1=CC=CC=C1 KMTDQMXKXXDKNT-UHFFFAOYSA-N 0.000 description 1
- FAMRKDQNMBBFBR-UHFFFAOYSA-N ethyl n-ethoxycarbonyliminocarbamate Chemical compound CCOC(=O)N=NC(=O)OCC FAMRKDQNMBBFBR-UHFFFAOYSA-N 0.000 description 1
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 description 1
- 229940093471 ethyl oleate Drugs 0.000 description 1
- XIWBSOUNZWSFKU-UHFFFAOYSA-N ethyl piperidine-3-carboxylate Chemical compound CCOC(=O)C1CCCNC1 XIWBSOUNZWSFKU-UHFFFAOYSA-N 0.000 description 1
- VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 description 1
- 229960005420 etoposide Drugs 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 208000021045 exocrine pancreatic carcinoma Diseases 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000003885 eye ointment Substances 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 239000010685 fatty oil Substances 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 238000007667 floating Methods 0.000 description 1
- 239000007850 fluorescent dye Substances 0.000 description 1
- 229960002949 fluorouracil Drugs 0.000 description 1
- MKXKFYHWDHIYRV-UHFFFAOYSA-N flutamide Chemical compound CC(C)C(=O)NC1=CC=C([N+]([O-])=O)C(C(F)(F)F)=C1 MKXKFYHWDHIYRV-UHFFFAOYSA-N 0.000 description 1
- 229960002074 flutamide Drugs 0.000 description 1
- 230000004907 flux Effects 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 230000037406 food intake Effects 0.000 description 1
- OSVMTWJCGUFAOD-KZQROQTASA-N formestane Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CCC2=C1O OSVMTWJCGUFAOD-KZQROQTASA-N 0.000 description 1
- 229960004421 formestane Drugs 0.000 description 1
- 239000012737 fresh medium Substances 0.000 description 1
- 206010017758 gastric cancer Diseases 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 239000003862 glucocorticoid Substances 0.000 description 1
- 229940050410 gluconate Drugs 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 229960002913 goserelin Drugs 0.000 description 1
- 239000003979 granulating agent Substances 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- 230000009036 growth inhibition Effects 0.000 description 1
- JEGUKCSWCFPDGT-UHFFFAOYSA-N h2o hydrate Chemical compound O.O JEGUKCSWCFPDGT-UHFFFAOYSA-N 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000010224 hepatic metabolism Effects 0.000 description 1
- 239000008131 herbal destillate Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000000265 homogenisation Methods 0.000 description 1
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 1
- 239000000017 hydrogel Substances 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000008311 hydrophilic ointment Substances 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 229960001330 hydroxycarbamide Drugs 0.000 description 1
- RIMIDGSPFGJFCN-UHFFFAOYSA-N hydroxymethyl benzoate Chemical compound OCOC(=O)C1=CC=CC=C1 RIMIDGSPFGJFCN-UHFFFAOYSA-N 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 229940031704 hydroxypropyl methylcellulose phthalate Drugs 0.000 description 1
- 229920003132 hydroxypropyl methylcellulose phthalate Polymers 0.000 description 1
- 230000036031 hyperthermia Effects 0.000 description 1
- 238000009217 hyperthermia therapy Methods 0.000 description 1
- 230000002519 immonomodulatory effect Effects 0.000 description 1
- 230000007124 immune defense Effects 0.000 description 1
- 230000001900 immune effect Effects 0.000 description 1
- 238000009169 immunotherapy Methods 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 238000001764 infiltration Methods 0.000 description 1
- 230000008595 infiltration Effects 0.000 description 1
- 239000003978 infusion fluid Substances 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 230000010354 integration Effects 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 238000009830 intercalation Methods 0.000 description 1
- 201000002313 intestinal cancer Diseases 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 229960004768 irinotecan Drugs 0.000 description 1
- GURKHSYORGJETM-WAQYZQTGSA-N irinotecan hydrochloride (anhydrous) Chemical compound Cl.C1=C2C(CC)=C3CN(C(C4=C([C@@](C(=O)OC4)(O)CC)C=4)=O)C=4C3=NC2=CC=C1OC(=O)N(CC1)CCC1N1CCCCC1 GURKHSYORGJETM-WAQYZQTGSA-N 0.000 description 1
- 239000000644 isotonic solution Substances 0.000 description 1
- 201000010982 kidney cancer Diseases 0.000 description 1
- 150000003893 lactate salts Chemical class 0.000 description 1
- 229940039717 lanolin Drugs 0.000 description 1
- 210000002429 large intestine Anatomy 0.000 description 1
- 150000002605 large molecules Chemical class 0.000 description 1
- 210000000867 larynx Anatomy 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- QDLAGTHXVHQKRE-UHFFFAOYSA-N lichenxanthone Natural products COC1=CC(O)=C2C(=O)C3=C(C)C=C(OC)C=C3OC2=C1 QDLAGTHXVHQKRE-UHFFFAOYSA-N 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 239000012669 liquid formulation Substances 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 201000005296 lung carcinoma Diseases 0.000 description 1
- 230000014759 maintenance of location Effects 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
- 230000003211 malignant effect Effects 0.000 description 1
- 208000006178 malignant mesothelioma Diseases 0.000 description 1
- 230000000873 masking effect Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 201000001441 melanoma Diseases 0.000 description 1
- SGDBTWWWUNNDEQ-LBPRGKRZSA-N melphalan Chemical compound OC(=O)[C@@H](N)CC1=CC=C(N(CCCl)CCCl)C=C1 SGDBTWWWUNNDEQ-LBPRGKRZSA-N 0.000 description 1
- 229960001924 melphalan Drugs 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 229960001428 mercaptopurine Drugs 0.000 description 1
- JABGXPCRNXUENL-UHFFFAOYSA-N mercaptopurine Chemical compound S=C1N=CNC2=NC=N[C]12 JABGXPCRNXUENL-UHFFFAOYSA-N 0.000 description 1
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-M methanesulfonate group Chemical class CS(=O)(=O)[O-] AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- OLXYLDUSSBULGU-UHFFFAOYSA-N methyl pyridine-4-carboxylate Chemical compound COC(=O)C1=CC=NC=C1 OLXYLDUSSBULGU-UHFFFAOYSA-N 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 1
- 239000004530 micro-emulsion Substances 0.000 description 1
- 239000003094 microcapsule Substances 0.000 description 1
- 239000004200 microcrystalline wax Substances 0.000 description 1
- 235000019808 microcrystalline wax Nutrition 0.000 description 1
- 239000011859 microparticle Substances 0.000 description 1
- 229960004857 mitomycin Drugs 0.000 description 1
- KKZJGLLVHKMTCM-UHFFFAOYSA-N mitoxantrone Chemical compound O=C1C2=C(O)C=CC(O)=C2C(=O)C2=C1C(NCCNCCO)=CC=C2NCCNCCO KKZJGLLVHKMTCM-UHFFFAOYSA-N 0.000 description 1
- 229960001156 mitoxantrone Drugs 0.000 description 1
- ODLGWKQRVMBKJS-UHFFFAOYSA-N n,n-diphenyl-4-[4-(3-pyridin-2-ylprop-2-enoylamino)butyl]piperidine-1-carboxamide Chemical compound C=1C=CC=NC=1C=CC(=O)NCCCCC(CC1)CCN1C(=O)N(C=1C=CC=CC=1)C1=CC=CC=C1 ODLGWKQRVMBKJS-UHFFFAOYSA-N 0.000 description 1
- VAFHQVDHXXZGHU-UHFFFAOYSA-N n-(6-aminohexyl)-1-benzhydrylpiperidine-3-carboxamide Chemical compound C1C(C(=O)NCCCCCCN)CCCN1C(C=1C=CC=CC=1)C1=CC=CC=C1 VAFHQVDHXXZGHU-UHFFFAOYSA-N 0.000 description 1
- NHPWMGBLZWTHLN-UHFFFAOYSA-N n-(6-aminohexyl)-1-benzhydrylpiperidine-3-carboxamide;dihydrochloride Chemical compound Cl.Cl.C1C(C(=O)NCCCCCCN)CCCN1C(C=1C=CC=CC=1)C1=CC=CC=C1 NHPWMGBLZWTHLN-UHFFFAOYSA-N 0.000 description 1
- MTWXSHXETKQKSN-UHFFFAOYSA-N n-[(1-benzhydryl-2h-azet-3-yl)methyl]-3-pyridin-3-ylprop-2-enamide Chemical compound C=1C=CN=CC=1C=CC(=O)NCC(C1)=CN1C(C=1C=CC=CC=1)C1=CC=CC=C1 MTWXSHXETKQKSN-UHFFFAOYSA-N 0.000 description 1
- APXKSEGWSPJKQA-UHFFFAOYSA-N n-[4-(1-benzylpiperidin-3-yl)butyl]-3-pyridin-3-ylprop-2-enamide Chemical compound C=1C=CN=CC=1C=CC(=O)NCCCCC(C1)CCCN1CC1=CC=CC=C1 APXKSEGWSPJKQA-UHFFFAOYSA-N 0.000 description 1
- OZDDODZSMNLZCZ-UHFFFAOYSA-N n-[4-(1-methylsulfonylpiperidin-4-yl)butyl]-3-pyridin-3-ylprop-2-enamide Chemical compound C1CN(S(=O)(=O)C)CCC1CCCCNC(=O)C=CC1=CC=CN=C1 OZDDODZSMNLZCZ-UHFFFAOYSA-N 0.000 description 1
- WJXXCPFHNISDFK-UHFFFAOYSA-N n-[4-(1-naphthalen-2-ylsulfonylpiperidin-4-yl)butyl]-5-pyridin-3-ylpenta-2,4-dienamide Chemical compound C1CN(S(=O)(=O)C=2C=C3C=CC=CC3=CC=2)CCC1CCCCNC(=O)C=CC=CC1=CC=CN=C1 WJXXCPFHNISDFK-UHFFFAOYSA-N 0.000 description 1
- GRTBFFDLPDANJH-UHFFFAOYSA-N n-[4-[1-(3,3-diphenylpropanoyl)piperidin-4-yl]butyl]-3-pyridin-3-ylprop-2-enamide Chemical compound C=1C=CN=CC=1C=CC(=O)NCCCCC(CC1)CCN1C(=O)CC(C=1C=CC=CC=1)C1=CC=CC=C1 GRTBFFDLPDANJH-UHFFFAOYSA-N 0.000 description 1
- LHLISGADCPGLQW-UHFFFAOYSA-N n-naphthalen-1-yl-4-[4-(3-pyridin-3-ylprop-2-enoylamino)butyl]piperidine-1-carboxamide Chemical compound C1CN(C(=O)NC=2C3=CC=CC=C3C=CC=2)CCC1CCCCNC(=O)C=CC1=CC=CN=C1 LHLISGADCPGLQW-UHFFFAOYSA-N 0.000 description 1
- 239000002105 nanoparticle Substances 0.000 description 1
- OPECTNGATDYLSS-UHFFFAOYSA-N naphthalene-2-sulfonyl chloride Chemical compound C1=CC=CC2=CC(S(=O)(=O)Cl)=CC=C21 OPECTNGATDYLSS-UHFFFAOYSA-N 0.000 description 1
- 229940100662 nasal drops Drugs 0.000 description 1
- 229940086322 navelbine Drugs 0.000 description 1
- 235000021313 oleic acid Nutrition 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 239000005022 packaging material Substances 0.000 description 1
- 229960001592 paclitaxel Drugs 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 238000002638 palliative care Methods 0.000 description 1
- 208000008443 pancreatic carcinoma Diseases 0.000 description 1
- 208000003154 papilloma Diseases 0.000 description 1
- 208000029211 papillomatosis Diseases 0.000 description 1
- 239000003182 parenteral nutrition solution Substances 0.000 description 1
- 238000005192 partition Methods 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 229940021222 peritoneal dialysis isotonic solution Drugs 0.000 description 1
- 238000005191 phase separation Methods 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical compound C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 description 1
- 150000003053 piperidines Chemical class 0.000 description 1
- 238000007747 plating Methods 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 229920001983 poloxamer Polymers 0.000 description 1
- 239000004584 polyacrylic acid Substances 0.000 description 1
- 239000004633 polyglycolic acid Substances 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 229920002223 polystyrene Polymers 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000003825 pressing Methods 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- XJMOSONTPMZWPB-UHFFFAOYSA-M propidium iodide Chemical compound [I-].[I-].C12=CC(N)=CC=C2C2=CC=C(N)C=C2[N+](CCC[N+](C)(CC)CC)=C1C1=CC=CC=C1 XJMOSONTPMZWPB-UHFFFAOYSA-M 0.000 description 1
- 201000001514 prostate carcinoma Diseases 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- GLVAUDGFNGKCSF-UHFFFAOYSA-N purine-6-thione Natural products S=C1NC=NC2=C1NC=N2 GLVAUDGFNGKCSF-UHFFFAOYSA-N 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 230000002285 radioactive effect Effects 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- ZAHRKKWIAAJSAO-UHFFFAOYSA-N rapamycin Natural products COCC(O)C(=C/C(C)C(=O)CC(OC(=O)C1CCCCN1C(=O)C(=O)C2(O)OC(CC(OC)C(=CC=CC=CC(C)CC(C)C(=O)C)C)CCC2C)C(C)CC3CCC(O)C(C3)OC)C ZAHRKKWIAAJSAO-UHFFFAOYSA-N 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 206010038038 rectal cancer Diseases 0.000 description 1
- 208000020615 rectal carcinoma Diseases 0.000 description 1
- 238000001226 reprecipitation Methods 0.000 description 1
- 230000000979 retarding effect Effects 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
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 239000013049 sediment Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- QFJCIRLUMZQUOT-HPLJOQBZSA-N sirolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 QFJCIRLUMZQUOT-HPLJOQBZSA-N 0.000 description 1
- 229960002930 sirolimus Drugs 0.000 description 1
- 201000000849 skin cancer Diseases 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- HELHAJAZNSDZJO-OLXYHTOASA-L sodium L-tartrate Chemical compound [Na+].[Na+].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O HELHAJAZNSDZJO-OLXYHTOASA-L 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- 239000001433 sodium tartrate Substances 0.000 description 1
- 229960002167 sodium tartrate Drugs 0.000 description 1
- 235000011004 sodium tartrates Nutrition 0.000 description 1
- 238000000935 solvent evaporation Methods 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 125000006850 spacer group Chemical group 0.000 description 1
- 210000000952 spleen Anatomy 0.000 description 1
- 210000004989 spleen cell Anatomy 0.000 description 1
- 238000001694 spray drying Methods 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 201000011549 stomach cancer Diseases 0.000 description 1
- 150000003890 succinate salts Chemical class 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
- 239000002511 suppository base Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 230000009897 systematic effect Effects 0.000 description 1
- 229940037128 systemic glucocorticoids Drugs 0.000 description 1
- QJJXYPPXXYFBGM-SHYZHZOCSA-N tacrolimus Natural products CO[C@H]1C[C@H](CC[C@@H]1O)C=C(C)[C@H]2OC(=O)[C@H]3CCCCN3C(=O)C(=O)[C@@]4(O)O[C@@H]([C@H](C[C@H]4C)OC)[C@@H](C[C@H](C)CC(=C[C@@H](CC=C)C(=O)C[C@H](O)[C@H]2C)C)OC QJJXYPPXXYFBGM-SHYZHZOCSA-N 0.000 description 1
- 229960001967 tacrolimus Drugs 0.000 description 1
- 229960001603 tamoxifen Drugs 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 150000003892 tartrate salts Chemical class 0.000 description 1
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 1
- 229940063683 taxotere Drugs 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
- RRVXZLSGEQVYGY-UHFFFAOYSA-N tert-butyl n-(1-aminohexyl)carbamate Chemical compound CCCCCC(N)NC(=O)OC(C)(C)C RRVXZLSGEQVYGY-UHFFFAOYSA-N 0.000 description 1
- 210000001550 testis Anatomy 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 229960001196 thiotepa Drugs 0.000 description 1
- 230000009974 thixotropic effect Effects 0.000 description 1
- 201000002510 thyroid cancer Diseases 0.000 description 1
- 229940044693 topoisomerase inhibitor Drugs 0.000 description 1
- 229960000303 topotecan Drugs 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
- 238000002054 transplantation Methods 0.000 description 1
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 150000003672 ureas Chemical class 0.000 description 1
- 210000004291 uterus Anatomy 0.000 description 1
- 210000001215 vagina Anatomy 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 1
- 229960004528 vincristine Drugs 0.000 description 1
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 1
- CILBMBUYJCWATM-PYGJLNRPSA-N vinorelbine ditartrate Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O.OC(=O)[C@H](O)[C@@H](O)C(O)=O.C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC CILBMBUYJCWATM-PYGJLNRPSA-N 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 230000003313 weakening effect Effects 0.000 description 1
- 229940100445 wheat starch Drugs 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
Classifications
-
- 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
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- 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
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/56—Amides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- 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
- C07D405/12—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 linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
- C07F9/576—Six-membered rings
- C07F9/59—Hydrogenated pyridine rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
- C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom
Definitions
- the invention relates to new pyridine compounds, methods for their production, medicaments containing these compounds as well as their use, especially in the treatment of tumor conditions and/or as cytostatic agents or as immunosuppressive agents.
- cytostatic therapy to provide new pharmaceuticals and/or medicaments which not only possess a strong activity, but also exert diminished side effects in comparison to many classical cancerostatic agents, whereby treatment of a broad as possible spectrum of tumors should be made accessible. Furthermore, effective cytostatic agents for an efficient therapy should be made available. Active ingredients of this type should also be exceptionally suitable in the mentioned indications for a combination therapy, be it in connection with other cytostatic agents or with radiation (for example X-rays, radioactive elements, such as cobalt, or linear accelerator, etc.), with operative procedures, heat treatment etc.
- radiation for example X-rays, radioactive elements, such as cobalt, or linear accelerator, etc.
- ⁇ -pyridyl alkane and/or alkene amides with anti-allergic activity are described in EP 0 210 782 which are referred to as having a 5-lipoxygenase-inhibiting and anti-histamine action, wherein the amide components of these compounds contain a piperazine or homopiperazine ring and the pyridine ring can be linked together in the 2-, 3- or 4-position.
- JP 63,179,869 describes further pyridyl amides, ⁇ -pyridyl alkane and alkene amides as anti-allergic effective substances containing a substituted piperidine ring in the amine component.
- Such compounds with the same properties are mentioned in Chem. Pharm. Bull 37, 100-105 (1989) and in J. Med. Chem. 1989, 583-593.
- Pyridyl ureas, pyridyl thioureas and pyridyl carbonamides, wherein the amide portion is bound over an aryl substituted alkyl chain with a piperidine ring or piperazine ring, are described for example in EP-A-0 428 434 or in EP-A-0 512 902 as antagonists of the neurokinin receptor and substance P.
- pyridyl(alkyl)carbonamides, pyridyl(alkyl)sulfonamides and analogous ureas, wherein the amide portion is bound over an alkyl chain with a piperidine ring are disclosed in EP-A-0 479 601 as active ingredients with anti-arrhythmic properties.
- WO 91/15 485 the production of pyridine-3,5-dicarboxylic acid esters and amides as well as their use for the treatment of tumor conditions is described. These compounds differ from the compounds according to the invention described below in very important structural features, for example by the dicarboxyl grouping on the pyridine ring or the absence of the hydrocarbon chain between the pyridine ring and the amide grouping.
- the compounds disclosed in WO 89/07 443 in the form of optically pure R( ⁇ )-Ni-guldipine and further analogous dihydropyridines with cytotoxic activity have larger structural differences. As compared to these known compounds, the compounds according to the invention unexpectedly possess a better activity and a wider spectrum of action despite the large structural differences.
- Structurally closely related compounds are represented by the piperidine compounds described in EP-A-0 330 026.
- no 3-pyridyl derivatives were concretely described and no concrete examples were disclosed in this publication, aside from a single compound which is described below.
- These known compounds are distinguished by anti-cholinesterase activity, an anti-amnesia activity as well as activities directed against hyperkinesis, senile dementia, mania and Alzheimer's disease.
- subject-matter of the invention relates to compounds of formula (I)
- any aryl residues and/or aromatic ring systems in the substituents R 1 , R 2 , R 4 , R 12 , R 13 , R 14 , R 15 , Ar 1 and Ar 2 and/or in the ring system —NR 12 R 14 can be substituted independently from each other by one to three of the same or different residues which are selected from halogen, cyano, alkyl, especially C 1 -C 6 -alkyl, trifluoromethyl, cycloalkyl, especially C 3 -C 8 -cycloalkyl, phenyl, benzyl, hydroxy, alkoxy, especially C 1 -C 6 -alkoxy, alkoxy, substituted entirely or partially by fluorine, substituted alkoxy especially C 1 -C 6 -alkoxy, benzyloxy, phenoxy, mercapto, alkylthio, especially C 1 -C 6 -alkylthio, carboxy, alkoxycarbonyl, especially C 1 -
- a preferred embodiment according to the invention relates to compounds of formula (I)
- aromatic ring systems in the substituents R 1 , R 2 , R 4 , R 12 , R 13 , R 14 , R 15 , Ar 1 and Ar 2 and/or in the ring system —NR 12 R 14 can be substituted independently from each other by one to three of the same or different residues which are selected from halogen, cyano, C 1 -C 6 -alkyl, trifluoromethyl, C 3 -C 8 -Cycloalkyl, phenyl, benzyl, hydroxy, C 1 -C 6 -alkoxy, which can optionally be entirely or partially substituted by fluorine, benzyloxy, phenoxy, mercapto, C 1 -C 6 -alkylthio, carboxy, C 1 -C 6 -alkoxycarbonyl, benzyloxycarbonyl, nitro, amino, mono-C 1 -C 6 -alkylamino or di-(C 1 -C 6 -alkylamino and
- a further preferred embodiment of the invention constitutes compounds of the invention, which are distinguished in that substituents R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 12 , R 13 , R 14 and R 15 as well as A and D labelled therein have the following meaning in connection with the given substitutions according to this formula
- halogen is fluorine, chlorine, bromine or iodine
- C 1 -C 6 -alkyl can be straight chain or branched and is preferably a methyl-, ethyl-, propyl-, isopropyl-, butyl-, isobutyl-, sec-butyl-, tert-butyl-, cyclopropylmethyl-, pentyl-, isopentyl-, tert-pentyl-, neopentyl-, cyclopropylethyl-, cyclobutylmethyl- or a hexyl group,
- alkylene is for example methylene, ethylene, propylene, tetraethylene, pentamethylene, hexamethylene, heptamethylene, octamethylene, nonamethylene or decamethylene,
- C 3 -C 6 -alkenyl can be straight chain or branched and is preferably an allyl-, 2-butenyl-, 3-butenyl-, 2-methyl-2-propenyl-, 2-pentenyl-, 4-pentenyl-, 2-methyl-2-butenyl-, 3-methyl-2-butenyl-, 2-hexenyl-, 5-hexenyl-, 4-methyl-3-pentenyl- or 2,2-dimethyl-3-butenyl group,
- alkenylene is for example ethenylene, propenylene, butenylene, pentenylene, hexenylene, hexathenylene, heptenylene, octenylene, nonenylene or decenylene,
- C 3 -C 6 -alkinyl can be straight chain or branched and is preferably a propargyl-, 2-butinyl-, 3-butinyl-, 4-pentinyl-, 5-hexinyl- or 4-methyl-2-pentinyl group,
- alkinylene is for example propenylene, butenylene, pentenylene, hexenylene, heptenylene, octenylene, nonenylene or decenylene,
- C 3 -C 8 -cycloalkyl is preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl,
- C 1 -C 6 -alkylamino contains one of the C 1 -C 6 -alkyl groups mentioned above, especially in form of the methylamino-, ethylamino-, propylamino-, isopropylamino-, butylamino- and the tert-butylamino group,
- di-(C 1 -C 6 -alkyl)amino carries two of the same or different of the above named C 1 -C 6 -alkyl groups on the nitrogen atom, especially in form of the dimethylamino-, diethylamino-, dipropylamino-, diisopropylamino-, isopropylmethylamino-, dibutylamino- or tert-butylmethylamino group,
- C 1 -C 6 -acyl is the residue of an aliphatic saturated or unsaturated, straight chain, branched or cyclic carboxylic acid, especially in form of the formyl-, acetyl-, propionyl-, acryloyl-, butyryl-, isobutyryl-, methacryloyl-, cyclopropylcarbonyl-, pentanoyl-, pivaloyl-, cyclobutylcarbonyl-, hexanoyl- and the dimethylacryloyl group,
- C 1 -C 6 -alkansulfonyl is preferably the methanesulfonyl-, ethanesulfonyl-, propanesulfonyl-, butanesulfonyl-, pentanesulfonyl- and the hexanesulfonyl group,
- saturated five- to seven-membered heterocycles with one or two hetero-atoms are especially tetrahydrofuryl, tetrahydrothienyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, hexahydroazepinyl, piperazinyl, hexahydrodiazepinyl or morpholinyl,
- monocyclic aromatic five- or six-membered heterocycles with one to three hetero-atoms are especially furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl or triazinyl,
- anellated bi- and tricyclic aromatic or partially hydrated carbocycle ring systems with 8 to 16 ring atoms and at least one aromatic are preferably benzocyclobutyl, indanyl, indenyl, naphthyl, dihydronaphthyl, tetrahydronaphthyl, biphenylenyl, fluorenyl, anthryl, dihydroanthryl, phenanthryl, dihydrophenanthryl, dibenzocycloheptenyl, dihydrodibenzocycloheptenyl, dihydrodibenzocyclooctenyl or tetrahydrodibenzocyclooctenyl, wherein mono- or dioxo-derivates, wherein the residues of indanone, tetralone, anthrone, anthraquinone, fluorenone, phenanthrone, dibezocycloheptenone, dihydrodibenz
- anellated bi- and tricyclic aromatic or partially hydrated heterocyclic ring systems with 8 to 16 ring atoms and at least one aromatic ring are, for example, imidazothiazolyl, benzofuryl, dihydrobenzofuryl, benzothienyl, dihydrobenzothienyl, indolyl, indolinyl, benzimidazolyl, indazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzofurazanyl, benzothiadiazolyl, benzotriazolyl, oxazolopyridyl, thiazolopyridyl, isothiazolopyridyl, imidazopyridyl, pyrazolopyridyl, thienopyrimidinyl, chromanyl, benzopyranyl, quinolyl, isoquinolyl, dihydroquinolyl, tetrahydro
- saturated and unsaturated monocyclic, four- to eight-membered heterocycles represent —NR 12 R 14 as a grouping which, aside from the essential nitrogen atom, can optionally contain one or two further hetero-atoms selected from N and/or S and/or O, for example azetidine, pyrrolidine, piperidine, (1H)tetrahydropyridine, hexahydroazepine, (1H)tetrahydroazepine, octahydroazocine, pyrazolidine, piperazine, hexahydrodiazepine, morpholine, hexahydrooxazepine, thiomorpholine or thiomorpholine-1,1-dioxide,
- azetidine pyrrolidine, piperidine, (1H)tetrahydropyridine, hexahydroazepine, (1H)tetrahydroazepine, octahydroazocine, pyrazolidine
- saturated or unsaturated bi- or tricyclic, anellated or bridged heterocycles with 8 to 16 ring atoms represent —NR 12 R 14 as a grouping which, aside from the essential nitrogen atom optionally contain one or two further hetero-atoms, selected from N and/or S and/or O, for example 5-aza-bicyclo[2.1.1]hexane, 2-aza-bicyclo[2.2.1]heptane, 7-aza-bicyclo[2.2.1]heptane, 2,5-diaza-bicyclo[2.2.1]heptane, 2-aza-bicyclo[2.2.2]octane, 8-aza-bicyclo[3.2.1]octane, 2,5-diaza-bicyclo[2.2.2]octane, 9-aza-bicyclo[3.3.1]nonane, indoline, isoindoline, (1H)-dihydroquinoline, (1H)-tetrahydroquinoline, (2H)-tetrahydr
- stereoisomers such as, if applicable, cis/trans-isomers, endo/exo-isomers, optic isomers such as enantiomers, diasteromers as pure isomers or mixtures and/or racemic mixtures as well as the pharmacologically acceptable acid addition salts with inorganic or organic acids, wherein the hydrochlorides, hydrobromides, hydroiodides, sulfates and phosphates, are preferred as addition salts with suitable inorganic acids and acetates, benzoates, citrates, fumarates, gluconates, malates, maleates, methanesulfonates, lactates, oxalates, succinates, tartrates and tosylates are preferred as addition salts of organic acids.
- a further preferred embodiment of the invention is in compounds which are distinguished in that the labelled substituents in formula (I)
- Reactive derivatives of compound (II) can be, for example, activated esters, anhydrides, acid halides (especially acid chlorides) or simple low alkyl esters.
- Suitable activated esters are, for example, p-nitrophenyl ester, 2,4,6-trichlorophenyl ester, pentachlorophenyl ester, cyanomethyl ester, esters of N-hydroxysuccinimide, of N-hydroxyphthalimides, of 1-hydroxybenzotriazol, of N-hydroxypiperidine, of 2-hydroxypyridine or of 2-mercaptopyridine, etc.
- Anhydrides can be symmetric anhydrides or mixed, as they are obtained, for example, with pivaloyl chloride or with chloroformates.
- Aromatic for example chloroformic phenyl ester
- araliphatic for example chloroformic benzyl ester
- aliphatic chloroformates for example chloroformic methyl ester, -ethyl ester or -isobutyl ester
- Reaction of compounds (II) with compounds (III) can also be carried out in the presence of condensation agents such as dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, N,N′-carbonyldiimidazol, 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline, etc.
- condensation agents such as dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, N,N′-carbonyldiimidazol, 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline, etc.
- condensation agent such as dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, N,N′-carbonyld
- Compounds of formula (III) can be used for reaction as free bases as well as in the form of their acid addition salts.
- the salts of inorganic acids are to be preferred, i.e. hydrochlorides, hydrobromides or sulfates.
- the reaction is optionally carried out in the presence of an auxiliary base.
- auxiliary base Suitable examples for this are alkali metal carbonates (sodium carbonate, potassium carbonate), alkali metal hydrogen carbonates (sodium hydrogen carbonate, potassium hydrogen carbonate), or organic bases such as, for example, triethylamine, ethyl diisopropylamine, tributylamine, N-methylmorpholine or pyridine.
- a suitable excess of compound (III) can also be used as a base. If compounds (III) are used in form of their acid addition salts, then it is appropriate to consider the amount of auxiliary base used as equivalent.
- reaction temperatures can—depending on reactivity of the educts—vary in a wide range. Generally, the reaction is carried out at temperatures between ⁇ 40° C. and 180° C., preferably between ⁇ 10° C. and 130° C., especially at the boiling point of the solvent used.
- the starting compounds (II) and (III) are known and/or can be produced according to known methods in an analogous manner. Moreover, the production of representative examples is further described below.
- nucleofuge or reactive group L represents a suitable nucleofuge or reactive group.
- the type of nucleofuge or reactive group L and the conditions of the reaction are dependent of the nature of group G.
- a reactive group L can also be an epoxide group, wherein the reaction occurs under addition.
- reaction of compounds (I), in which G is a hydrogen, and (IV) is usually conducted in a suitably inert solvent.
- solvents of this type aromatic hydrocarbons (benzene, toluene, xylene), ethers (for example tetrahydrofuran, dioxane, glycol dimethyl ether), ethyl acetate, acetonitrile, ketones (acetone, ethyl methyl ketone), polar protic solvents such as alcohols (ethanol, isopropanol, butanol, glycol monomethyl ether) or polar aprotic solvents such as, for example, dimethylsulfoxide, dimethylformamide or N-methylpyrrolidone can be considered.
- G is an acyl residue, carbamoyl residue, sulfonyl residue or phosphinoyl residue according to definition, or their derivatives capable of reaction.
- Preferred derivatives of carboxylic acids and/or sulfonic acids (V) which are capable of reaction are symmetric or unsymmetric carboxylic acid anhydrides and/or sulfonic acid anhydrides or acyl- and/or sulfonyl halides, especially acyl- and/or sulfonyl chlorides.
- derivatives of carbonates and/or phosphinic acids which are capable of reaction are the carbamoyl halides and/or phosphinyl halides, especially carbamyl- and/or phosphinyl chlorides.
- the reaction of the acids (V) and/or their reactive derivatives with compounds (I), in which G is hydrogen, preferably occurs in the presence of auxiliary bases in solvents and under conditions as they are described in method (a).
- R 12 and R 14 and/or the grouping —NR 12 R 14 have the meanings according to the above definitions without having to purify or isolate the intermediate product.
- Bis-trichloromethyl carbonate (triphosgene) and carbonyldiimidazol have been proven as particularly reactive carbonyl group transmitters.
- the reaction of compounds of formula (I), wherein G is hydrogen, with triphosgene and/or carbonyldiimidazol are typically conducted in an absolute, inert solvent in the presence of a tertiary organic amine as an auxiliary base in such a manner that the solution of compounds (I) and the auxiliary base are slowly poured into a solution of an equivalent amount of carbonyl group transmitter.
- the reaction requires molar ratios of 1:1 for the reaction of compound (I) and carbonyldiimidazol, and, in contrast, a ratio of 1:0.35 for the use of triphosgene.
- Suitable inert solvents are, for example hydrocarbons such as hexane, heptane, benzene, toluene, xylene, chlorinated hydrocarbons (for example dichloromethane, chloroform, 1,2-dichloroethane, trichloroethylene), ethers (for example diethyl ether, tetrahydrofuran, dioxane), esters such as ethyl acetate, butyl acetate, acetonitrile or polar aprodic solvents such as formamide or dimethylformamide.
- hydrocarbons such as hexane, heptane, benzene, toluene, xylene
- chlorinated hydrocarbons for example dichloromethane, chloroform, 1,2-dichloroethane, trichloroethylene
- ethers for example diethyl ether, tetrahydrofuran, dioxane
- Pure solvents as well as mixtures can be used diversely. Sometimes it is of advantage to carry out the first partial reaction at low temperature in a low-viscosity, highly-volatile solvent and to remove the solvent after formation of the intermediate and replace it by a higher boiling solvent.
- Amines such as for example triethylamine, ethyl diisopropylamine, tributylamine, N-methylmorpholine or pyridine are suitable as auxiliary bases. If compounds (I) or (VI) are used as salts, the amount of the auxiliary base is increased accordingly.
- the reaction temperatures can lie in between ⁇ 40° C. and 50° C. for the first partial reaction, preferably at 0° C. to 30° C., and between 0° C. and 150° C. for the second partial reaction, preferably at 20° C. to 120° C.
- reaction of the compounds of formula (I), in which G is hydrogen, with the isocyanates of formula (VII) are conducted thereby in an absolute, inert solvent which can be a hydrocarbon such as pentane, hexane, heptane, benzene, toluene, or xylene, chlorinated hydrocarbons (such as dichloromethane, chloroform, 1,2-dichloroethane, trichloroethylene), ethers (for example, diethyl ether, tetrahydrofuran, dioxane), esters such as ethyl acetate, butyl acetate, or polar aprotic solvents such as formamide or dimethylformamide. mixtures of various solvents can also be used.
- the reaction temperatures can vary in the region from ⁇ 20° C. to 150° C., but preferably lie at 20° C. to 100° C.
- the compounds of formula (I), wherein G is hydrogen are themselves compounds with tumor growth inhibiting activity and/or cytostatic and immunosuppressive effectiveness. However, independent of their therapeutic applicability, they also represent useful intermediate compounds for the production of a multitude of other compounds according to the invention corresponding to (c) to (f).
- compounds of formula (I), in which G is hydrogen are essentially more advantageously produced from other compounds of formula (I), in which G is a selectively cleavable group under mild conditions, i.e. corresponds to a nitrogen protective group.
- G represents a 4-methoxybenzyl group, a triphenylmethyl group, a methoxy- and/or ethoxycarbonyl group, a tert-butoxycarbonyl group, an allyloxycarbonyl group or a trifluoroacetyl group.
- compounds of formula (I) with a 4-methoxybenzyl group as G are transformed into compounds of formula (I) with hydrogen as G by selective oxidation with ammonium-cer(IV)-nitrate for example.
- R 4 is an alkyl, alkenyl, alkinyl or cycloalkyl residue according to the above definition and L is a suitable nucleofuge, i.e. for example a halogen atom such as chlorine, bromine or iodine or a sulfonic acid ester of an alcohol.
- Preferred sulfonic acid esters (VIII) contain a methylsulfonyloxy residue, trifluoromethanesulfonyloxy-, p-toluenesulfonyloxy-, p-bromobenzensulfonyloxy- or m-nitrobenzenesulfonyloxy residue as L.
- auxiliary bases such as potassium-tert-butylate, sodium hydride, potassium hydride or butyl lithium in aprotic, inert solvents.
- solvents can be for example aliphatic or aromatic hydrocarbons (pentane, hexane, heptane, benzene, toluene), ethers (for example, tetrahydrofuran, dioxane) or polar solvents such as dimethylsulfoxide, dimethylformamide or N-methylpyrrolidone.
- the reaction temperatures can lie between ⁇ 40° C. and 140° C. preferably between ⁇ 20° C. and 80° C.
- the compounds of formula (I) produced according to the methods (a) to (g) can be isolated and purified in a known manner, for example by subjecting the residue after distillation of the solvent to partition, extraction, re-precipitation or re-crystallization or another purification method. For this, column chromatography on a suitable support or preparative, middle or high pressure liquid chromatography are preferred for this.
- the compounds (I) are first normally obtained in form of their free bases or their hydrates or solvates, depending on the type of isolation and purification. Their addition salts with pharmaceutically suitable acids are obtained in a typical manner by converting the base with the desired acid in a suitable solvent. Depending on the number of basic centers of compound (I), one or more equivalent acids per mole of base can be bound.
- Suitable solvents are, for example, chlorinated hydrocarbons such as dichloromethane or chloroform; ethers such as diethyl ether, dioxane or tetrahydrofuran; acetonitrile; ketones such as acetone or ethyl methyl ketone; esters such as methyl acetate or ethyl acetate or low molecular alcohols such as methanol, ethanol or isopropanol; and water. Pure solvents as well as mixtures of two or three solvents can also be used.
- the salts can be isolated by crystallization, precipitation or the evaporation of the solvent. Thereby, they optionally accumulate as hydrates or solvates.
- the bases can be recovered from the salts by alkalization, for example with aqueous ammonia solution, alkali carbonate or diluted sodium hydroxide solution.
- CDI carbonyldiimidazol
- EDC N-(3-dimethylaminopropyl)-N′-ethyl-carbodiimide hydrochloride
- TEA triethylamine
- the reaction mixture is washed with 10% sodium hydroxide solution.
- the aqueous phase is extracted twice, each with 50 ml dichlormethane.
- the combined organic phases are dried over sodium sulfate and the solvent is removed under vacuum.
- the residue is chromatographically pre-purified over silica gel with CHCl 3 /CH 3 OH (98/2 to 95/5) and subsequently purified by two-fold flash-chromatography with CHCl 3 /CH 3 OH (99/1 to 95/5).
- an amorphous solid remains with a MP of 72-74° C.; yield: 0.75 g (7%).
- the mixture is stirred for two hours at RT and extracted by shaking three times in the heat each with 10 ml water, 2 M sodium hydroxide and water again.
- the organic phase is concentrated under vacuum and the orange colored oily residue is chromatographically purified twice over silica gel with CHCl 3 /CH 3 OH/NH 4 OH (90/9/1 and 95/5/0 to 90/10/0) and crystallized from 10 ml acetic acid ethyl ester. Colorless crystals remain with a MP of 100-102° C.; yield: 1.9 g (35%).
- the batch is washed twice with sodium hydroxide with 50 ml 2M sodium hydroxide solution and 70 ml water.
- the organic phase is dried over sodium sulfate and the solvent is removed under vacuum.
- the residue is chromatographically purified over silica gel with CHCl 3 /CH 3 OH (96/4 to 95/5) and crystallized from 70 ml acetonitrile. Colorless crystals remain with a MP of 129-131° C.; yield: 3.9 g (62%).
- the reaction time is prolonged to 6 hours at RT.
- the batch is washed with 50 ml 1 M sodium hydroxide solution and the aqueous phase is extracted with 50 ml dichlormethane.
- the combined organic phases are concentrated under vacuum and the residue is chromatographically pre-purified twice over silica gel with CHCl 3 /CH 3 OH (93/7 and 95/5), subsequently purified further by flash-chromatography with CHCl 3 /CH 3 OH (95/5 and 97/3) and crystallized from 5 ml acetic acid ethyl ester. Colorless crystals remain with a MP of 80-82° C.; yield: 0.9 g (15%).
- the residue is chromatographically purified over silica gel with CHCl 3 /CH 3 OH (100/0 to 98/2) and dissolved in 80 ml ethanol. After addition of 6 ml conc. hydrochloric acid, the mixture is heated to boiling for 5 hours. After cooling, the solvent is removed under vacuum and the residue is azeotropically dehydrated twice, each with 30 ml toluene, and subsequently dried under high-vacuum. The resin is further processed without additional purification Yield: 6.8 g (71%).
- the aqueous phase is made basic with 200 ml 10% sodium hydroxide solution and extracted twice each with 250 ml toluene.
- the solvent is removed under vacuum and the residue is chromatographically purified over silica gel with CHCl 3 /CH 3 OH (97/3). After drawing off the solvent, a light brown oil remains which is processed further without additional purification. Yield: 47.4 g (90%).
- the active ingredients according to the invention can be processed to the desired medicaments in the form of their acid addition salts, hydrates or solvates individually or in combination with each other, optionally under addition of other active ingredient, for the indications tumor treatment or immunosuppression.
- these can also optionally be separately present next to each other in the medicine packaging, for example as tablets next to vials, depending on the requirements.
- further subject-matter of the invention is a method for the treatment of the human or animal body in which a compound or compound mixture according to formula (I), wherein the substituents have the above described meaning, is administered for treatment of tumors and/or as a cytostatic agent, cancerostatic agent, immunosuppressing agent, optionally in combination with further cytostatic or immunosuppressive active ingredients or other active ingredients suitable in the named indications.
- the invention relates to a compound or compound mixture according to formula (I) for use in a therapeutic method in which the therapeutic use is carried out in connection with one or more medical indications with tumors or for immunosuppression, optimally in combination with further pharmaceuticals suitable in the named indications.
- a method for the production of medicaments with an amount of one or more compounds according to formula (I) which are suitable for the processing of these active ingredients together with respective suitable pharmaceutically acceptable carriers and adjuvants for finished medicinal forms equally belongs to the scope of protection according to the invention.
- the respective suitable medical form is selected for the suitable therapeutic application.
- the invention also relates to the use of the compounds according to formula (I), including (E)-3-(3-pyridyl)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-2-propenamide hydrochloride, for treatment in the above indications.
- medicaments with an amount of one or more compounds according to the invention and/or their use in the application according to the invention occurs in the customary manner by means of common pharmaceutical technology methods.
- the active ingredients as such or in the form of their salts are processed together with suitable, pharmaceutically acceptable adjuvants and carriers to medicinal forms suitable for the various indications and types of application.
- the medicaments can be produced in such a manner that the respective desired release rate is obtained, for example a quick flooding and/or a sustained or depot effect.
- injections are administered for the treatment of tumors.
- These are prepared either in the form of vials or also as so-called ready-to-use injection preparations, for example as ready-to-use syringes or single use syringes in addition to perforation bottles for multiple withdrawals.
- Administration of the injection preparations can occur in the form of subcutaneous (s.c.), intramuscular (i.m.), intravenous (i.v.) or intracutaneous (i.c.) application.
- the respective suitable injection forms can especially be produced as solutions, crystal suspensions, nanoparticular or colloid-disperse systems, such as for example, hydrosols.
- the injectable formulations can also be produced as concentrates which can be adjusted with aqueous isotonic dilution agents to the desired active ingredient dosage. Furthermore, they can also be produced as powders, such as for example lyophilisates, which are then preferably dissolved or dispersed immediately before application with suitable diluents.
- the infusions can also be formulated in the form of isotonic solutions, fat emulsions, liposome formulations, microemulsions and liquids based on mixed micells, for example, based on phospholipids.
- infusion formulations can also be prepared in the form of concentrates to dilute.
- the injectable formulations can also be applied in the form of continuous infusions as in stationary as well as in out-patient therapy, for example in the form of mini-pumps.
- Albumin, plasma expanders, surface active compounds, organic solvents, pH influencing compounds, complex forming compounds or polymeric compounds can be added to the parenteral medicinal forms, especially as substances for influencing the adsorption of the active ingredients to protein or polymers or also with the aim of decreasing the adsorption of the active ingredient to materials such as injection instruments or packaging materials, for example plastic or glass.
- the active ingredients can be bound to nanoparticles in the preparations for parenteral use, for example on finely dispersed particles based on poly(meth)acrylates, polyacetates polyglycolates, polyamino acids or polyether urethanes.
- the parenteral formulations can also be constructively modified as depot preparations, for example on the multiple unit principle, where the active ingredients are incorporated in a most finely distributed and/or dispersed, suspended form or as crystal suspensions, or on the single unit principle, where the active ingredient is enclosed in a medicinal form, for example, a tablet or a seed which is subsequently implanted.
- these implantations or depot medicaments in single unit and multiple unit medicinal forms consist of so-called biodegradable polymers, such as for example, polyether urethanes of lactic and glycolic acid, polyether urethanes, polyamino acids, poly(meth)acrylates or polysaccharides.
- biodegradable polymers such as for example, polyether urethanes of lactic and glycolic acid, polyether urethanes, polyamino acids, poly(meth)acrylates or polysaccharides.
- Sterilized water pH value influencing substances, such as for example organic and inorganic acids or bases as well as their salts, buffer substances for setting the pH value, agents for isotonicity, such as for example sodium chloride, monosodium carbonate, glucose and fructose, tensides and/or surface active substances and emulsifiers, such as for example, partial fatty acid esters of polyoxyethylene sorbitan (Tween®) or for example fatty acid esters of polyoxethylene (Cremophor®), fatty oils such as for example peanut oil, soybean oil and castor oil, synthetic fatty acid esters, such as for example ethyl oleate, isopropyl myristate and neutral oil (Miglyol®) as well as polymer adjuvants such as for example gelatin, dextran, polyvinylpyrrolidone, organic solvent additives which increase solubility, such as for example propylene glycol, ethanol, N,N-dimethylacetamide
- thickening agents to prevent the settling of the active ingredients from tensides and peptizers, to sure the ability of the sediment to be shaken, or complex formers, such as EDTA, ensues.
- This can also be achieved with the various polymeric agent complexes, for example with polyethylene glycols, polystyrol, carboxymethylcellulose, Pluronics® or polyethylene glycol sorbitan fatty acid esters.
- the active ingredient can also be incorporated in liquid formulations in the form of inclusion compounds, for example with cyclodextrins.
- dispersion agents are also suitable.
- builders are also used, such as for example mannite, dextran, saccharose, human albumin, lactose, PVP or gelatin varieties.
- the active ingredients are not incorporated in the liquid medicinal formulations in the form of a base, they are used in the form of their acid addition salts, hydrates or solvates in the preparations for parenteral use.
- a further systemic application form of importance is peroral administration as tablets, hard or soft gelatin capsules, coated tablets, powders, pellet, microcapsules, oblong compressives, granules, chewable tablets, lozenges, gums or sachets.
- These solid peroral administration forms can also be prepared as sustained action and/or depot systems.
- film or matrix forming substances such as for example ethylcellulose, hydroxypropylmethylcellulose, poly(meth)acrylate derivatives (for example Eudragit®), hydroxypropylmethylcellulose phthalate are suitable in organic solutions as well as in the form of aqueous dispersions.
- bio-adhesive preparations are also to be named in which the increased retention time in the body is achieved by intensive contact with the mucus membranes of the body.
- An example of a bio-adhesive polymer is the group of Carbomers®.
- compressives such as for example non-disintegrating tablets in oblong form of a suitable size with a slow release of active ingredient
- compressives are especially suitable.
- mixtures of pellets which release at the various places are employable, for example of gastric fluid soluble and small intestine soluble and/or gastric fluid resistant and large intestine soluble pellets.
- the same goal of releasing at various sections of the gastrointestinal tract can also be conceived by suitably produced laminated tablets with a core, whereby the coating of the agent is quickly released in gastric fluid and the core of the agent is slowly released in the small intestine milieu.
- the goal of controlled release at various sections of the gastrointestinal tract can also be attained by multilayer tablets.
- the pellet mixtures with differentially released agent can be filled into hard gelatin capsules.
- Anti-stick and lubricant and separating agents such as flame dispersed silicone dioxide, disintegrants, such as various starch types, PVC, cellulose ester as granulating or retarding agents, such as for example wax-like and/or polymeric compounds on the basis of Eudragit®, cellulose or Cremophor® are used as a further adjuvants for the production of compressives, such as for example tablets or hard and soft gelatin capsules as well as coated tablets and granulates.
- dispersion agents such as flame dispersed silicone dioxide, disintegrants, such as various starch types, PVC, cellulose ester as granulating or retarding agents, such as for example wax-like and/or polymeric compounds on the basis of Eudragit®, cellulose or Cremophor® are used as a further adjuvants for the production of compressives, such as for example tablets or hard and soft gelatin capsules as well as coated tablets and granulates.
- Ant-oxidants sweetening agents, such as for example saccharose, xylite or mannite, masking flavors, aromatics, preservatives, colorants, buffer substances direct tableting agents, such as for example microcrystalline cellulose, starch and starch hydrolystates (for example Celutab®), lactose, polyethylene glycols, polyvinylpyrrolidone and dicalcium phosphate, lubricants, fillers, such as lactose or starch, binding agents in the form of lactose, starch varieties, such as for example wheat or corn and/or rice starch, cellulose derivatives, for example methylcellulose, hydroxypropylcellulose or silica, talcum powder, stearates, such as for example magnesium stearate, aluminum stearate, calcium stearate, talc, siliconized talc, stearic acid, acetyl alcohol and hydrated fats are used.
- tableting agents such as for example microcrystalline cellulose, starch and starch hydroly
- oral therapeutic system constructed especially on osmotic principles, such as for example GIT (gastrointestinal therapeutic system) or OROS (oral osmotic system), are also to be mentioned.
- GIT gastrointestinal therapeutic system
- OROS oral osmotic system
- Effervescent tablets or tabs both of which represent immediately drinkable instant medicinal forms which are quickly dissolved or suspended in water are among the perorally administratable compressives.
- perorally administratable forms are also solutions, for example drops, juices and suspensions, which can be produced according to the above given method, and can still contain preservatives for increasing stability and optionally aromatics for reasons of easier intake, and colorants for better differentiation as well as antioxidants and/or vitamins and sweeteners such as sugar or artificial sweetening agents. This is also true for inspisated juices which are formulated with water before ingestion.
- Ion exchange resins in combination with one or more active ingredients are also to be mentioned for the production of liquid ingestable forms.
- a special release form consists in the preparation of so-called floating medicinal forms, for example based on tablets or pellets which develop gas after contact with body fluids and therefore float on the surface of the gastric fluid.
- so-called electronically controlled release systems can also be formulated by which active ingredient release can be selectively adjusted to individual needs.
- a further group of systemic administration and also optionally topically effective medicinal forms are represented by rectally applicable medicaments.
- suppositories and enema formulations.
- the enema formulations can be prepared based on tablets with aqueous solvents for producing this administration form.
- Rectal capsules can also be made available based on gelatin or other carriers.
- Hardened fat such as for example Witepsol®, Massa Estarium®, Novata®, coconut fat, glycerol-gelatin masses, glycerol-soap-gels and polyethylene glycols are suitable as suppository bases.
- pressed implants are suitable which are preferably formulated on the basis of so-called biodegradable polymers.
- transdermal systems are also to be emphasized which distinguish themselves, as with the above-mentioned rectal forms, by circumventing the liver circulation system and/or liver metabolism.
- These plasters can be especially prepared as transdermal systems which are capable of releasing the active ingredient in a controlled manner over longer or shorter time periods based on different layers and/or mixtures of suitable adjuvants and carriers.
- membrane infiltration increasing substances and/or permeation promoters such as for example oleic acid, Azone®, adipinic acid derivatives, ethanol, urea, propylglycol are suitable in the production of transdermal systems of this type for the purpose of improved and/or accelerated penetration.
- vaginally or genitally applicable emulsions creams, foam tablets, depot implants, ovular or transurethral administration installation solutions.
- highly sterile eye ointments, solutions and/or drops or creams and emulsions are suitable.
- otological drops, ointments or creams can be designed for application to the ear.
- semi-solid formulations such as for example gels based on Carbopols® or other polymer compounds such as for example polyvinylpyrolidone and cellulose derivatives is also possible.
- Sodium algenate as a gel builder for production of a suitable foundation or cellulose derivatives such as for example guar or xanthene gum
- inorganic gel builders such as for example aluminum hydroxides or bentonites (so-called thixotropic gel builder)
- polyacrylic acid derivatives such as for example Carbopol®, polyvinylpyrolidone, microcrystalline cellulose or carboxymethylcellulose are suitable as adjuvants and/or carriers.
- amphiphilic low and high molecular weight compounds as well as phospholipids are suitable.
- the gels can be present either as hydrogels based on water or as hydrophobic organogels, for example based on mixtures of low and high molecular paraffin hydrocarbons and vaseline.
- Anionic, cationic or neutral tensides can be employed as emulsifiers, for example alkalized soaps, methyl soaps, amine soaps, sulfonated compounds, cationic soaps, high fatty alcohols, partial fatty acid esters of sorbitan and polyoxyethylene sorbitan, for example lanette types, wool wax, lanolin, or other synthetic products for the production of oil/water and/or water/oil emulsions.
- Hydrophilic organogels can be formulated, for example, on the basis of high molecular polyethylene glycols. These gel-like forms are washable.
- Osmotically effective acids and bases such as for example hydrochloric acid, citric acid, sodium hydroxide solution, potassium hydroxide solution, monosodium carbonate, further buffer systems, such as for example citrate, phosphate, Tris-buffer or triethanolamine are used for adjusting the pH value.
- Preservatives for example such as methyl- or propyl benzoate parabenes
- sorbic acid can be added for increasing stability.
- Pastes powders or solutions are to be mentioned as further topically applicable forms.
- Pastes often contain lipophilic and hydrophilic auxiliary agents with very high amounts of fatty matter as a consistency-giving base.
- Powders or topically applicable powders can contain for example starch varieties such as wheat or rice starch, flame dispersed silicon dioxide or silica, which also serve as diluents, for increasing flowability as well as lubricity as well as for preventing agglomerates.
- starch varieties such as wheat or rice starch
- flame dispersed silicon dioxide or silica which also serve as diluents, for increasing flowability as well as lubricity as well as for preventing agglomerates.
- Nose drops or nose sprays serve as nasal application forms.
- nebulizers or nose crams or ointments can come to use.
- nose spray or dry powder formulations as well as controlled dosage aerosols are also suitable for systemic administration of the active ingredients.
- these pressure and/or controlled dosage aerosols and dry powder formulations can be inhaled and/or insufflated. Administration forms of this type also certainly have importance for direct, regional application in the lung or bronchi and larynx.
- the dry powder compositions can be formulated for example as active ingredient-soft pellets, as an active ingredient-pellet mixture with suitable carriers, such as for example lactose and/or glucose.
- suitable carriers such as for example lactose and/or glucose.
- suitable carriers such as for example lactose and/or glucose.
- suitable carriers such as for example lactose and/or glucose.
- suitable carriers such as for example lactose and/or glucose.
- suitable carriers such as for example lactose and/or glucose.
- suitable carriers such as for example lactose and/or glucose.
- suitable carriers such as for example lactose and/or glucose.
- suitable carriers such as for example lactose and/or glucose.
- suitable carriers such as for example lactose and/or glucose
- tetrafluoroethane or HFC 134a and/or heptafluoropropane or HFC 227 are suitable, wherein non-fluorinated hydrocarbons or other propellants which are gaseous at normal pressure and room temperature, such as for example propane, butane or dimethyl ether can be preferred.
- propellant-free, manual pump systems can also be used.
- the propellant gas aerosols can also suitably contain surface active adjuvants, such as for example isopropyl myristate, polyoxyethylene sorbitan fit acid ester, sorbitan trioleate, lecithins or soya lecithin.
- surface active adjuvants such as for example isopropyl myristate, polyoxyethylene sorbitan fit acid ester, sorbitan trioleate, lecithins or soya lecithin.
- solutions for installation for example for transurethral administration in bladder tumors or genital tumors, or for profusion in liver tumors or other organ carcinomas are suitable.
- the respective suitable medicinal forms can be produced in accordance with the prescription and procedures based on pharmaceutical-physical fundamentals as they are described for example in the following handbooks and are included in the present inventive subject-matter with respect to the production of the respective suitable medicaments:
- the solution is produced according to the customary method, sterilized and filled into 10 ml vials.
- One vial contains 50 mg of the compound according to the invention.
- Penteral Solution active ingredient used according to the invention 1.000 g hydrochloric acid, dilute 5.000 g sodium chloride 6.000 g water for injection purposes to 1000.000 ml
- the solution is produced according to a customary method by stirring; the medicinal form is adjusted to a suitable pH value by acid addition and subsequently filled into 100 ml vials and sterilized.
- a vial contains 100 mg of the compound according to the invention.
- Parenteral Dispersion active ingredient used according to the invention 10.000 g soya lecithin 20.000 g saturated triglycerides 100.000 g sodium hydroxide 7.650 g water for injection purposes to 1000.000 ml
- the active ingredient(s) used according to the invention is dispersed in the saturated triglycerides. Then the soya lecithin is added under stirring, ad subsequent to this, the aqueous solution of sodium hydroxide is added with subsequent homogenization. The dispersion is sterilized and filled into 10 ml vials. A vial contains 50 mg of the compound according to the invention.
- Biodegradable Parenteral Depot Medicinal Form active ingredient used according to the invention 10.000 polylactic acid /polygylcolic acid polymer 70.000 polyvinylpyrrolidone 0.200 gelatin 2.000 soya lecithin 2.000 isotonic sodium chloride solution to 1000.000 ml
- the active ingredient is incorporated into the biodegradable polymer comprising polylactic acid and polyglycolic acid by a suitable method (spray drying, solvent-evaporation or phase separation) and subsequently subjected to a sterilization process.
- the particles are introduced into a 2-chamber ready-made syringe in which the adjuvant solution, which is also produced in a sterile manner, is filled.
- the biodegradable microparticles are mixed with the dispersion agent shortly before application and dispersed.
- a ready-made syringe contains 200 mg of the active compound according to the invention.
- the active ingredient is dispersed together with soya lecithin and arachis oil.
- the benzyl alcohol is dissolved in Miglyole® and added to the dispersion.
- the entire dispersion is sterilized and subsequently filled into vials with 2 ml content
- a vial contains 50 mg active ingredient.
- the solution named under example b) can also be used for perfusion of liver for example.
- inked of ampules with injection solution so-called perforation bottles (vials), which can also be optionally preserved, and infusion solutions with an amount of one or more active ingredients according to the invention can also be made available in the customary manner under addition of buffer substances for adjustment of physiological pH value and/or the isotonicity and/or a best possible suitable pH value for the medicinal form (euhydria) and optional further required nutrients, vitamins, amino acids, stabilizers and other necessary adjuvants, possibly in combination with further medicinal agents suitable for the mentioned indications.
- buffer substances for adjustment of physiological pH value and/or the isotonicity and/or a best possible suitable pH value for the medicinal form (euhydria) and optional further required nutrients, vitamins, amino acids, stabilizers and other necessary adjuvants, possibly in combination with further medicinal agents suitable for the mentioned indications.
- the above components are mixed with each other and compacted in a conventional manner, wherein a tablet weight of ISO mg is set. Each tablet contains 100 mg active ingredient. If desired, the tablets obtained in this manner are coated, provided with a film coat and/or enterically coated.
- Coated Tablet Core active ingredient used according to the invention 10,000 g flame dispersed silicon dioxide 500 g corn starch 2,250 g stearic acid 350 g ethanol 3.0 l gelatin 900 g purified water 10.0 l talcum 300 g magnesium stearate 180 g
- a granulate is produced which is pressed to the desired coated tablet cores.
- Each core contains 50 mg of active ingredient.
- the core can be further processed in a customary manner to coated tablets. If desired, a gastric fluid resistant or retarding film coat can be applied in a known manner.
- the above-mentioned components are mixed in a customary manner to a suspension and filled in a suitable drink vial having 5 ml content.
- the active ingredient is compacted together with the adjuvants under high pressure to sublingual tablets, favorably in oblong form.
- Soft Gel Capsule active ingredient used according to the invention 0.050 g fatty acid glyceride mixture (Miglyole ®) q.s. to 0.500 g
- the active ingredient is impasted together with the fluid carrier mixture and mixed together with further adjuvants suitable for the encapsulation and filled into elastic soft gelatin capsules which are sealed.
- Hard Gelatin Capsules active ingredient used according to the invention 0.150 g microcrystalline cellulose 0.100 g hydroxypropylmethylcellulose 0.030 g mannite 0.100 g ethylcellulose 0.050 g triethyl citrate 0.010 g
- the active ingredient is mixed together with the adjuvants, microcrystalline cellulose, hydroxypropylmethylcellulose and mannite, wet with granulation liquid and formed into pellets. These are subsequently coated with a solution of ethylcellulose and triethyl citrate in organic solvents in a fluidized-bed apparatus
- a hard gelatin capsule contains 150 mg of active ingredient.
- Hydrophilic Ointment active ingredient used according to the invention 0.500 g Eucerinum ® anhydricum 60.000 g microcrystalline wax 15.000 g vaseline oil q.s. to 100.000 g
- Lipophilic Ointment active ingredient used according to the invention 10.000 g propylene glycol 50.000 g paraffin, liquid 100.000 g paraffin wax 100.000 g vaseline to 1000.000 ml
- the active ingredient(s) used according to the invention is dissolved in propylene glycol at ca. 60° C.
- the lipophilic components are melted at 60-70° C. mad subsequently combined with the active ingredient solution.
- the ointment is emulsified at first at 60-70° C. and subsequently cooled to 35-40° C. under constant emulsification and then filled in 10 g tubes, A tube contains 100 mg of the compound according to the invention.
- compositions which is characterized in that it contains an active ingredient(s) used according to the invention as a base or a physiologically acceptable salt thereof together with carriers and/or diluents customary for this and suitable for administration by means of inhalation.
- physiologically acceptable salts of the active ingredients are, as already illustrated in the synthesis section, acid addition salts derived from inorganic or organic acids such as for example especially hydrochloride, hydrobromide, sulfate, phosphate, maleate, tartrate, citrate, benzoate, 4-methoxybenzoate, 2- or 4-hydroxybenzoate, 4 chlorobenzoate, p-tosylate, methanesulfonate, ascorbate, salicylate, acetate, formate, succinate, lactate, glutarate, gluconate or tricarballylate.
- inorganic or organic acids such as for example especially hydrochloride, hydrobromide, sulfate, phosphate, maleate, tartrate, citrate, benzoate, 4-methoxybenzoate, 2- or 4-hydroxybenzoate, 4 chlorobenzoate, p-tosylate, methanesulfonate, ascorbate, salicylate, acetate, formate, succinate, lac
- the administration of the active ingredient(s) used of the invention by means of inhalation occurs according to the invention in conventional ways customary for administrations of this form, for example in the form of a commercial controlled dosage aerosol or in combination with a spacer.
- a metering valve is delivered with whose help, a dosed amount of the composition is administered.
- the present compositions can be formulated for example as aqueous solutions or suspensions and be administered by means of an atomizer.
- Aerosol spray formulations in which the active ingredient is either suspended with one or two stabilizers in a propellant as a carrier and/or diluent, for example tetrafluoroethane or HFC 134a and/or heptafluoropropane or HFC 227 can equally be used, whereby however, non-fluorinated hydrocarbons or other propellants which are gaseous at normal pressure and room temperature, such as propane, butane or dimethyl ether, can be preferred. Thereby, propellant-free manual pump system or dry powder systems as described below can also be used.
- the propellant aerosols can also contain surface active adjuvants, such as for example isopropyl myristate, polyoxyethylene sorbitan fatty acid ester, sorbitan trioleate, lecithins, oleic acid.
- surface active adjuvants such as for example isopropyl myristate, polyoxyethylene sorbitan fatty acid ester, sorbitan trioleate, lecithins, oleic acid.
- the medicaments with an amount of compounds according to the invention can also be formulated in the form of dry powder compositions, for example as active ingredient-soft pellets or as an active ingredient-powder mixture with a suitable carrier, such as for example lactose and/or glucose.
- a suitable carrier such as for example lactose and/or glucose.
- the powder compositions can be formulated and administered as single doses or as multiple doses.
- the compounds according to the invention are preferably administered by means of a controlled dosage aerosol or in the form of a dry powder dosage formulation, wherein the latter preferably contains glucose and/or lactose as a carrier substance.
- all applicators are generally suitable which are suitable for controlled dosage aerosols and/or a dry powder dosage formulation, such as for example usual applicators for the nose, mouth and or pharynx, or also devices standing under propellant gas for the delivery of a spray (as controlled dosage aerosol or dry powder dosage formulation) as they are also used for inhalations in the nose, mouth and/or pharynx.
- a further embodiment can also consist of an aqueous solution of the active ingredient(s) used according to the invention, which also optionally contains further active ingredients and/or additives, which are applied by means of an ultrasound atomizer.
- Aerosol Intended dose per aerosol per stroke % by weight active ingredient used according 0.500 mg 0.66 to the invention stabilizer 0.075 mg 0.10 HFC 134a 75.500 mg 99.24
- Aerosol Intended dose per aerosol per stroke % by weight active ingredient used according 0.250 mg 0.32 to the invention Stabilizer 0.038 mg 0.05 HFC 227 79.180 mg 99.63
- the micronized active ingredient is, after previous dispersion in a small amount of the stabilizer, placed in a suspension vessel in which the bulk amount of propellant gas solution is found.
- the corresponding suspension is dispersed by means of a suitable stirring system (for example high performance mixer or ultrasound mixer) until an ultra-fine dispersion results.
- the suspension is then continuously held in flux in a filling apparatus suitable for cold propellants or pressure fillings.
- the suspension can also be produced in a suitable cooled stabilizer solution in HFC 134a/227.
- Dosage-Dry Powder Formulation mg/dose active ingredient used according to the invention 0.500 mg lactose Ph.Eur. to 2.5 mg or to 5.0 mg
- Dosage-Dry Powder Formulation mg/dose active ingredient used according to the invention 0.250 mg lactose Ph.Eur. to 2.5 mg or to 5.0 mg
- the active ingredient is formulated after micronization under addition of stem as pellets with an MMAD between 0.1 and 0.3 mm diameter and brought to use in a multi-dose powder applicator.
- the active ingredient is micronized, thereafter, bulk material is mixed with the lactose in the given amounts, and subsequently, filled in a multi-dose powder inhalator.
- the active ingredient or the medicinal agent in the form of the respective suitable pharmaceutical acceptable salt and/or acid addition salts can be present, insofar as the base is not preferred in each case.
- the tumor growth inhibiting activity of the substances was determined on human tumor cells in standardized in vitro test systems. In the screening tests, the substances gave IC 50 -values in a concentration range of 0.1 nM to 10 ⁇ M.
- FCS fetal calf serum
- test was added and the protein amount in the individual wells was determined with the sulforhodamine-B-method (according to P. Skehan et al.: New Colorimetric Cytotoxicity Assay for Anticancer-Drug Screening J. Natl. Cancer Inst. 82: 1107-1112, 1990).
- IC 50 -values (defined as that concentration in which the cell growth was inhibited by 50%) was taken from the dose response curves and given as a comparative measurement for the activity of the test compounds.
- the compounds of formula (I) and their salts permit a therapeutic use in malignant illness of humans and animals through their excellent inhibition of the growth of tumor cells.
- the anti-neoplastic activity of the described substances can be used for prophylactic, adjunct, palliative, and curative treatment of solid tumors, leukemic illnesses and lymphomas as well as for decreasing or preventing metastasis formation in humans and animals.
- gynecological tumors such as of the uterus or the vagina, ovarian carcinomas, testicle tumors, prostate carcinomas, skin cancer, kidney cancer, bladder tumors, esophagus carcinomas, stomach cancer, rectal carcinomas, pancreas carcinomas, thyroid cancer, adrenal tumors, leukemia and lymphomas
- Hodgkin's disease tumor illnesses of the CNS, soft-tissue sarcomas, bone sarcomas, benign and malignant mesotheliomas, but especially intestine cancer, liver cancer, breast cancer, bronchial and lung carcinomas, melanomas, acute and chronic leukemias.
- Benign papillomatosis tumors are also considered for therapy with the named substances.
- the novel structural class of compounds possesses an independent activity profile in the effectiveness against the various tumor types.
- tumors which are resistant to customary cytostatic agents, for example can respond entirely to these substances.
- combinations of the new compounds with known chemo-therapeutically used pharmaceuticals or other methods of treatment are considered as long as their properties are complimented in a suitable manner.
- anti-metabolites for example cytarabine, 5-fluorouracil, 6 mercaptopurine, methotrexate
- alkylating agents for example busulfan, carmustine, cisplatin, carboplatin, cyclophosphamide, dacarbazine, melphalan, thiotepa
- DNA-intercalating substances and topoisomerase inhibitors for example actinomycin D, daunorubicin, doxorubicin, mitomycin C, mitoxantrone, etoposide, teniposide, topotecan, irinotecan
- spindle poisons for example vincristine, navelbine, taxol, taxotere
- hormonally active agents for example tamoxifen, flutamide, formestane, goserelin
- Resistant tumor cells can be made sensitive again by interaction of the new compounds with a mechanism of resistance for common cytostatic agents (for example P-glycoprotein, MRP, glutathione-S-transferase, metallothionein).
- cytostatic agents for example P-glycoprotein, MRP, glutathione-S-transferase, metallothionein.
- a combination is also applicable with radiation therapy, hyperthermia or immunotherapy, for example.
- the spleen of a Swiss mouse served as a lymphocyte source.
- the lymphocyte population was isolated from the spleen cell suspension over a ficoll gradient and taken up in IMEM-ZO culture medium with 0.1% dextran 70,000 and 2% fetal calf serum.
- the cells were plated at a density of CL 500,000-cells/well/ml in a 12-well plate, 1 ml doubly concentrate test substance solution was pipetted per well and this was subsequently incubated in a tissue culture incubator at 37° C. and 5% CO 2 .
- IC 50 -values were calculated which were also employed in the following Tables for the characterization of the individual substances: Test Substance No. IC 50 [ ⁇ M] 150 0.0002 153 0.00008 159 0.003 195 0.002 199 0.00004
- the independent class of the compounds used according to the invention also permits an efficient combination with known immunosuppressive agents such as for example cyclosporin A, tacrolimus, rapamycin, azathioprine and glucocorticoids.
- immunosuppressive agents such as for example cyclosporin A, tacrolimus, rapamycin, azathioprine and glucocorticoids.
- the invention is in no way limited to the present respective concretely named active ingredient concentrations, dosages, combinations with one or more other cytostatic agents, tumor inhibitors, cancerostatic agents, immunosuppressive agents or further medicinal agents suitable for the respective specific indications or the type of tumor to treated or immunological illness, etc.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Veterinary Medicine (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Molecular Biology (AREA)
- Pharmacology & Pharmacy (AREA)
- Biochemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Immunology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Transplantation (AREA)
- Hematology (AREA)
- Oncology (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyridine Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Catalysts (AREA)
Abstract
Description
- The invention relates to new pyridine compounds, methods for their production, medicaments containing these compounds as well as their use, especially in the treatment of tumor conditions and/or as cytostatic agents or as immunosuppressive agents.
- A pressing need exists for cytostatic therapy to provide new pharmaceuticals and/or medicaments which not only possess a strong activity, but also exert diminished side effects in comparison to many classical cancerostatic agents, whereby treatment of a broad as possible spectrum of tumors should be made accessible. Furthermore, effective cytostatic agents for an efficient therapy should be made available. Active ingredients of this type should also be exceptionally suitable in the mentioned indications for a combination therapy, be it in connection with other cytostatic agents or with radiation (for example X-rays, radioactive elements, such as cobalt, or linear accelerator, etc.), with operative procedures, heat treatment etc.
- In this connection, a strong need also exists to enrich tumor therapy with new compounds for overcoming or preventing resistances for example.
- This object was successfully solved in a completely surprising manner by making available the pyridyl alkane acid amide derivatives defined below.
- It was known that various pyridine compounds substituted in a specific manner have pharmacologically useful properties which lie however in completely different indication areas.
- Thus, ω-pyridyl alkane and/or alkene amides with anti-allergic activity are described in EP 0 210 782 which are referred to as having a 5-lipoxygenase-inhibiting and anti-histamine action, wherein the amide components of these compounds contain a piperazine or homopiperazine ring and the pyridine ring can be linked together in the 2-, 3- or 4-position. JP 63,179,869 describes further pyridyl amides, ω-pyridyl alkane and alkene amides as anti-allergic effective substances containing a substituted piperidine ring in the amine component. Such compounds with the same properties are mentioned in Chem. Pharm. Bull 37, 100-105 (1989) and in J. Med. Chem. 1989, 583-593.
- Pyridyl ureas, pyridyl thioureas and pyridyl carbonamides, wherein the amide portion is bound over an aryl substituted alkyl chain with a piperidine ring or piperazine ring, are described for example in EP-A-0 428 434 or in EP-A-0 512 902 as antagonists of the neurokinin receptor and substance P. Furthermore, pyridyl(alkyl)carbonamides, pyridyl(alkyl)sulfonamides and analogous ureas, wherein the amide portion is bound over an alkyl chain with a piperidine ring are disclosed in EP-A-0 479 601 as active ingredients with anti-arrhythmic properties.
- In WO 91/15 485, the production of pyridine-3,5-dicarboxylic acid esters and amides as well as their use for the treatment of tumor conditions is described. These compounds differ from the compounds according to the invention described below in very important structural features, for example by the dicarboxyl grouping on the pyridine ring or the absence of the hydrocarbon chain between the pyridine ring and the amide grouping. The compounds disclosed in WO 89/07 443 in the form of optically pure R(−)-Ni-guldipine and further analogous dihydropyridines with cytotoxic activity have larger structural differences. As compared to these known compounds, the compounds according to the invention unexpectedly possess a better activity and a wider spectrum of action despite the large structural differences.
- Structurally closely related compounds are represented by the piperidine compounds described in EP-A-0 330 026. However, no 3-pyridyl derivatives were concretely described and no concrete examples were disclosed in this publication, aside from a single compound which is described below. These known compounds are distinguished by anti-cholinesterase activity, an anti-amnesia activity as well as activities directed against hyperkinesis, senile dementia, mania and Alzheimer's disease.
- In view of this art, the finding that the compounds according to the genera formula (I) defined below have activities which make them particularly suitable in an excellent manner for the therapy of tumor illnesses was completely unexpected. The pharmacological finding that the compounds according to the invention also possess immunosuppressive properties besides cytostatic activity is to be considered as equally surprising.
- Pharmacological test results from which this conclusion must be drawn, as well as the concrete tumor indications and combination possibilities are detailed and illustrated in the last part of the description.
-
- wherein
- R1 is hydrogen, halogen cyano, trifluormethyl, hydroxy, benzyloxy, aminocarbonyl, carboxy, phenyl, phenoxy, phenylthio, pyridyloxy, pyridylthio, alkyl, especially C1-C6-alkyl, alkenyl, especially C3-C6-alkenyl, alkinyl, especially C3-C6-alkinyl, hydroxyalkyl, especially C1-C6-hydroxyalkyl, alkoxy, especially C1-C6-alkoxy, alkenyloxy, especially C3-C6-alkenyloxy, alkinyloxy, especially C3-C6-alkinyloxy, alkanoyloxy, especially C1-C7-alkanoyloxy, alkoxycarbonyloxy, especially C2-C7-alkoxycarbonyloxy, alkylthio, especially C1-C6-alkylthio, alkenylthio, especially C3-C6-alkenylthio, alkinylthio, especially C3-C6-alkinylthio, cycloalkyl, especially C3-C8-cycloalkyl, cycloalkyloxy, especially C3-C8-cycloalkyloxy, cycloalkylthio, especially C3-C8-cycloalkylthio, alkoxycarbonyl, especially C2-C7-alkoxycarbonyl, alkylaminocarbonyl, especially C2-C7-alkylaminocarbonyl, dialkylaminocarbonyl, especially C3-C13-dialkylaminocarbonyl, or NR5R6, wherein
- R5 and
- R6 are selected independently of each other from hydrogen, alkyl, especially C1-C6-alkyl, alkenyl, especially C3-C6-alkenyl and alkinyl, especially C3-C6-alkinyl,
- R2 is hydrogen, halogen, cyano, hydroxy, trifluoromethyl, benzyloxy, alkyl, especially C1-C6-alkyl, alkoxy, especially C1-C6-alkoxy or alkanoyloxy, especially C1-C7-alkanoyloxy,
- wherein R1 and R2, if they are adjacent, optionally form a bridge which is selected from
- (CH2)4—, —(CH═CH)2— and —CH2O—CR7R8—O—, wherein
- R7 and
- R8 are, independently of each other, hydrogen or alkyl, especially C1-C6-alkyl,
- R3 is hydrogen, halogen, alkyl, especially C1-C6-alkyl, trifluoromethyl or hydroxyalkyl, especially C1-C6-hydroxyalkyl and
- R4 is hydrogen, hydroxy, benzyloxy, alkyl, especially C1-C6-alkyl, alkenyl, especially C3-C6-alkenyl, alkinyl, especially C3-C6-alkinyl, cycloalkyl, especially C3-C6-cycloalkyl or alkoxy, especially C1-C6-alkoxy,
- k is 0 or 1,
- A is alkenylene, especially C2-C6-alkenylene, which is optionally substituted once to three-fold by C1-C3-alkyl, hydroxy, C1-C3-alkoxy, fluorine, cyano or phenyl,
- alkadienylene with at least four C-atoms, especially C4-C6-alkadienylene, which is optionally substituted once or twice by C1-C3-alkyl, fluorine, cyano or phenyl
- 1,3,5-hexatrienylene, which is optionally substituted by C1-C3-alkyl, fluorine, cyano, or phenyl,
- ethinylene
- D is selected from alkylene, especially C1-C10-alkylene, optionally substituted once or twice by alkyl, especially C1-C6-alkyl, hydroxy, or alkoxy, especially C1-C6-alkoxy,
- alkenylene with at least two C-atoms, especially C2-C10-alkenylene, which is optionally substituted once or twice by alkyl, especially C1-C6-alkyl, hydroxy, or alkoxy, especially C1-C6-alkoxy, wherein the double bond can also be to ring E,
- alkinylene with at least three C-atoms, especially C3-C10-alkinylene, optionally substituted once or twice by alkyl, especially C1-C6-alkyl, hydroxy or alkoxy, especially C1-C6-alkoxy, and
- alkylene, especially C1-C10-alkylene, alkenylene with at least two C-atoms, especially C2-C10-alkenylene or alkinylene with at least three C-atoms, especially C3-C10-alkinylene, whereby one to three methylene units are each isosterically replaced by O, S, NR9, CO, SO or SO2 wherein
- R9 is selected from hydrogen, alkyl, especially C1-C6-alkyl, alkenyl, especially C3-C6-alkenyl, alkinyl, especially C3-C6-alkinyl, acyl, especially C1-C6-acyl or alkylsulfonyl especially C1-C6-alkylsulfonyl,
- E is selected from
- wherein the heterocyclic ring can also optionally have a double bond and
- n and
- p can be, independently of one another, 0, 1, 2 or 3, with the proviso that n+p≦4 and
- q is 2 or 3,
- R10 is hydrogen, alkyl, especially C1-C6-alkyl, hydroxy, hydroxymethyl, carboxy or alkoxycarbonyl with at least two C-atoms, especially C2-C7-alkoxycarbonyl and
- R11 is hydrogen, alkyl, especially C1-C6-alkyl or an oxo group adjacent to the nitrogen atom, wherein
- R10 and R11 optionally together, form an alkylene bridge with 1, 2, 3, 4 or 5 C-atoms, especially a C1-C3-alkylene bridge under formation of a bicyclic ring system,
- G is selected from hydrogen,
- G1, G2, G3, G4 and G5, wherein
- G1 represents the residue
—(CH2)r—(CR13R14)s—R12 (G1) - wherein
- r is an integer from 1 to 3 or 0 and
- s is 0 or 1,
- R12 is selected from hydrogen, alkyl, especially C1-C6-alkyl, alkenyl with at least three C-atoms, especially C3-C6-alkenyl, alkinyl with at least three C-atoms, especially C3-C6-alkinyl, cycloalkyl with at least three C-atoms, especially C3-C8-cycloalkyl,
- saturated, five to seven membered heterocycles, which can contain one or two hetero-atoms from the group N and/or S and/or O,
- benzyl or phenyl,
- monocyclic aromatic five or six-membered heterocycles, which can contain one to three hetero-atoms from the group N and/or S and/or O and are either bound directly or over a methylene group,
- anellated bi- and tricyclic aromatic or partially hydrated carbocyclic ring systems with 8 to 16 ring atoms and at least one aromatic ring, wherein the linkage can occur either over an aromatic or a hydrated ring and either directly or over a methylene group,
- anellated bi- and tricyclic aromatic or partially hydrated heterocyclic ring systems with 8 to 16 ring atoms and at least one aromatic ring, wherein one to three ring atoms can be selected from N and/or S and/or O and the linkage can occur either over an aromatic or a hydrated ring and either directly or over a methylene group,
- R13 has the same meaning as R12, but is selected independently thereof,
- R14 is selected from hydrogen, hydroxy, methyl, benzyl, phenyl,
- monocyclic aromatic five or six-membered heterocycles, which can contain one to three hetero-atoms selected from the group N and/or S and/or O and are either bound directly or over a methylene group,
- anellated bi- and tricyclic aromatic or partially hydrated carbocyclic ring systems with 8 to 16 ring atoms and at least one aromatic ring, wherein the linkage can occur either over an aromatic or a hydrated ring and either directly or over a methylene group,
- anellated bi- and tricyclic aromatic or partially hydrated heterocyclic ring systems with 8 to 16 ring atoms and at least one aromatic ring, wherein one to three ring atoms can be selected from N and/or S and/or O and the linkage can occur either over an aromatic or a hydrated ring and either directly or over a methylene group,
- G2 is the residue
- wherein the substituents R12 and R14 can have the above meaning or the grouping
—NR12R14 - can also be a nitrogen heterocycle bond over the nitrogen atom, selected from
- saturated or unsaturated monocyclic, four- to eight-membered heterocycles, which, aside from the essential nitrogen atom, can optionally contain one or two further hetero-atoms selected from the group N and/or S and/or O, or
- saturated or unsaturated bi- or tricyclic, anellated, or bridged heterocycles with 8 to 16 ring atoms, which, aside from the essential nitrogen atom, can optionally contain one or two further hetero-atoms selected from the group N and/or S and/or O,
- wherein the substituents R12 and R14 can have the above meaning or the grouping
- G3 is the residue
—SO2—(CH2)rR12 (G3)- and
- G4 is the residue
- wherein
- Ar1 and Ar2 are selected independently from one another from phenyl, pyridyl or naphthyl and
- G5 is the residue
—COR15 (G5)- wherein
- R15 is selected from trifluoromethyl, alkoxy, especially C1-C6-alkoxy alkenyloxy, especially C3-C6-alkenyloxy, or benzyloxy,
- wherein any aryl residues and/or aromatic ring systems in the substituents R1, R2, R4, R12, R13, R14, R15, Ar1 and Ar2 and/or in the ring system —NR12R14 can be substituted independently from each other by one to three of the same or different residues which are selected from halogen, cyano, alkyl, especially C1-C6-alkyl, trifluoromethyl, cycloalkyl, especially C3-C8-cycloalkyl, phenyl, benzyl, hydroxy, alkoxy, especially C1-C6-alkoxy, alkoxy, substituted entirely or partially by fluorine, substituted alkoxy especially C1-C6-alkoxy, benzyloxy, phenoxy, mercapto, alkylthio, especially C1-C6-alkylthio, carboxy, alkoxycarbonyl, especially C1-C6-alkoxycarbonyl, benzyloxycarbonyl, nitro, amino, monoalkylamino, especially mono-C1-C6-alkylamino, dialkylamino, especially di-(C1-C6-alkyl)-amino and methylenedioxy for two adjacent groups on the aromatic ring or ring system,
- wherein each of the residues alkyl, alkenyl, alkinyl, hydroxyalkyl, alkoxy, alkenyloxy, alkinyloxy, alkanoyloxy, alkoxycarbonyl, alkoxycarbonyloxy, alkylthio, alkenylthio, alkinylthio, alkylene, acyl, alkylsulfonyl, alkenylene, alkinylene, cycloalkyl, cycloalkyloxy, alkoxycarbonyl, alkylaminocarbonyl or dialkylaminocarbonyl of the substituents R1 to R13 can have 1 to 2 or 4, 6, 8, 10 or 12 C-atoms and/or 2 or 3 to 5, 7, 9, 11 or 13 and/or 15 C-atoms or 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 C-atoms depending on the structure, as well as
- stereoisomers and/or mixtures thereof and pharmacologically acceptable
- acid addition salts thereof
- with the exception of (E)-3-(3-pyridyl)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-2-propenamide hydrochloride.
-
- wherein
- R1 is a hydrogen, halogen, cyano, C1-C6-alkyl, C3-C6-alkenyl, C3-C6-alkinyl, trifluoromethyl, C3-C6-cycloalkyl, C1-C6-hydroxyalkyl, hydroxy, C1-C6-alkoxy, C3-C6-alkenyloxy, C3-C6-alkinyloxy, benzyloxy, C1-C7-alkanoyloxy, C2-C7-alkoxycarbonyloxy, C1-C6-alkylthio, C3-C6-alkenylthio, C3-C6-alkinylthio, C3-C8-cycloalkyloxy, C3-C8-cycloalkylthio, C2-C7-alkoxycarbonyl, aminocarbonyl, C2-C7-alkylaminocarbonyl, C3-C13-dialkylaminocarbonyl, carboxy, phenyl, phenoxy, phenylthio, pyridyloxy, pyridylthio, or NR5R6, wherein
- R5 and
- R6 are selected independently from each other from hydrogen, C1-C6-alkyl, C3-C6-alkenyl and C3-C6-alkinyl,
- R2 is hydrogen, halogen, cyano, C1-C6-alkyl, trifluoromethyl, hydroxy, C1-C6-alkoxy, benzyloxy or C1-C7-alkanoyloxy,
- wherein R1 and R2, in case they are adjacent, optionally form a bridge which is selected from the bridge members
- —(CH2)4 and —(CH═CH)2— and —CH2O—CR7R8—O—, wherein
- R7 and
- R8 are, independently from each other, hydrogen or C1-C6-alkyl,
- R3 is hydrogen, halogen, C1-C6-alkyl, trifluoromethyl or C1-C6-hydroxyalkyl and
- R4 is hydrogen, C1-C6-alkyl, C3-C6-alkenyl, C3-C6-alkinyl, C3-C6-cycloalkyl, hydroxy, C1-C6-alkoxy or benzyloxy,
- k is 0 or 1,
- A is C2-C6-alkenylene, which is optionally substituted once to three-fold by C1-C3-alkyl, hydroxy, C1-C3-alkoxy, fluorine, cyano or phenyl,
- C4-C6-alkadienylene, which is optionally substituted once or twice by C1-C3-alkyl, fluorine, cyano or phenyl
- 1,3,5-hexatrienylene, which is optionally substituted by C1-C3-alkyl, fluorine, cyano or phenyl as well as
- ethinylene,
- D is selected from C1-C10-alkylene, optionally substituted once or twice by C1-C6-alkyl, hydroxy, or C1-C6-alkoxy,
- C2-C10-alkenylene, which is optionally substituted once or twice by C1-C6-alkyl, hydroxy, or C1-C6-alkoxy, wherein the double bond can also be to ring E,
- C3-C10-alkinylene, optionally substituted once or twice by C1-C6-alkyl, hydroxy, or C1-C6-alkoxy, and
- C1-C10-alkylene, C2-C10-alkenylene or C3-C10-alkinylene, wherein one to three methylene units are each isosterically replaced by O, S, NR9, CO, SO or SO2, wherein
- R9 is selected from hydrogen, C1-C6-alkyl, C3-C6-alkenyl, C3-C6-alkinyl, C1-C6-acyl or C1-C6-alkylsulfonyl,
- E is selected from
- wherein the heterocyclic ring can optionally have a double bond and
- n and
- p can be, independently of each other, 0, 1, 2 or 3, with the proviso that n+p≦4 and
- q is 2 or 3,
- R10 is hydrogen, C1-C6-alkyl, hydroxy, hydroxymethyl, carboxy or C2-C7-alkoxycarbonyl and
- R11 hydrogen, C1-C6-alkyl or an oxo group adjacent to the nitrogen atom, wherein
- R10 and R11 optionally together form a C1-C3-alkylene bridge under formation of a bi-cyclic ring system,
- G is selected from hydrogen,
- G1, G2, G3, G4 and G5, wherein
- G1 represents the residue
—(CH2)r—(CR13R14)—R12 (G1) - wherein
- r is an integer from 1 to 3 or 0 and
- s is 0 or 1,
- R12 is selected from hydrogen, C1-C6-alkyl, C3-C6-alkenyl, C3-C6-alkinyl, C3-C8-cycloalkyl,
- saturated, five- to seven-membered heterocycles, which can contain one or two hetero-atoms from the group N and/or S and/or O,
- benzyl or phenyl,
- monocyclic aromatic five or six-membered heterocycles, which can contain one to three hetero-atoms from the group N and/or S and/or O and are either bound directly or over a methylene group,
- anellated bi- and tricyclic aromatic or partially hydrated carbocyclic ring systems with 8 to 16 ring atoms and at least one aromatic ring, wherein the linkage can occur either over an aromatic or a hydrated ring and either directly or over a methylene group,
- anellated bi- and tricyclic aromatic or partially hydrated heterocyclic ring systems with 8 to 16 ring atoms and at least one aromatic ring, wherein one to three ring atoms can be selected from N and/or S and/or O and the linkage can occur either over an aromatic ring or a hydrated ring and either directly or over a methylene group,
- R13 has the same meaning as R12, but is selects independently thereof,
- R14 is selected from hydrogen, hydroxy, methyl, benzyl, phenyl,
- monocyclic aromatic five- or six-membered heterocycles, which can contain one to three hetero-atoms selected form the group N and/or S and/or O and are either bound directly or over a methylene group,
- anellated bi- and tricyclic aromatic or partially hydrated carbocyclic ring Systems with 8 to 16 ring atoms and at least one aromatic ring, wherein the linkage can occur either over an aromatic or a hydrated ring and either directly or over a methylene group,
- anellated bi- and tricyclic aromatic or partially hydrated heterocyclic ring systems with 8 to 16 ring atoms and at least one aromatic ring, wherein one to three ring atoms can be selected from N and/or S and/or O and the linkage can occur either over an aromatic ring or a hydrated ring and either directly or over a methylene group,
- G2 is the residue
- wherein the substituents R12 and R14 can have the above meaning or the grouping
—NR12R14 - can also be a nitrogen heterocycle bound over the nitrogen atom, selected from
- saturated or unsaturated monocyclic, four- to eight-membered heterocycles, which, aside from the essential nitrogen atom, can optionally contain one or two further hetero-atoms selected from the group N and/or S and/or O, or
- saturated or unsaturated bi- or tricyclic, anellated or bridged heterocycles with 8 to 16 ring atoms, which, aside from the essential nitrogen atom, can optionally contain one or two further hetero-atoms selected from the group N and/or S and/or O,
- wherein the substituents R12 and R14 can have the above meaning or the grouping
- G3 is the residue
—SO2—(CH2)rR12 (G3)- and
- G4 is the residue
- wherein
- Ar1 and Ar2 are selected independently from one another from phenyl, pyridyl or naphthyl and
- G5 is the residue
—COR15 (G5)- wherein
- R15 is selected from trifluoromethyl, C1-C6-alkoxy, C3-C6-alkenyloxy, or benzyloxy, and wherein
- aromatic ring systems in the substituents R1, R2, R4, R12, R13, R14, R15, Ar1 and Ar2 and/or in the ring system —NR12R14 can be substituted independently from each other by one to three of the same or different residues which are selected from halogen, cyano, C1-C6-alkyl, trifluoromethyl, C3-C8-Cycloalkyl, phenyl, benzyl, hydroxy, C1-C6-alkoxy, which can optionally be entirely or partially substituted by fluorine, benzyloxy, phenoxy, mercapto, C1-C6-alkylthio, carboxy, C1-C6-alkoxycarbonyl, benzyloxycarbonyl, nitro, amino, mono-C1-C6-alkylamino or di-(C1-C6-alkylamino and methylenedioxy for two adjacent groups on the aromatic ring or ring system,
- stereoisomers thereof and/or mixtures thereof and pharmacologically acceptable
- acid addition salts
- with the exception of (E)-3-(pyridyl)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-2-propenamide hydrochloride.
- A further preferred embodiment of the invention constitutes compounds of the invention, which are distinguished in that substituents R1, R2, R3, R4, R5, R6, R7, R8, R9, R12, R13, R14 and R15 as well as A and D labelled therein have the following meaning in connection with the given substitutions according to this formula
- wherein
- halogen is fluorine, chlorine, bromine or iodine,
- C1-C6-alkyl can be straight chain or branched and is preferably a methyl-, ethyl-, propyl-, isopropyl-, butyl-, isobutyl-, sec-butyl-, tert-butyl-, cyclopropylmethyl-, pentyl-, isopentyl-, tert-pentyl-, neopentyl-, cyclopropylethyl-, cyclobutylmethyl- or a hexyl group,
- alkylene is for example methylene, ethylene, propylene, tetraethylene, pentamethylene, hexamethylene, heptamethylene, octamethylene, nonamethylene or decamethylene,
- C3-C6-alkenyl can be straight chain or branched and is preferably an allyl-, 2-butenyl-, 3-butenyl-, 2-methyl-2-propenyl-, 2-pentenyl-, 4-pentenyl-, 2-methyl-2-butenyl-, 3-methyl-2-butenyl-, 2-hexenyl-, 5-hexenyl-, 4-methyl-3-pentenyl- or 2,2-dimethyl-3-butenyl group,
- alkenylene is for example ethenylene, propenylene, butenylene, pentenylene, hexenylene, hexathenylene, heptenylene, octenylene, nonenylene or decenylene,
- C3-C6-alkinyl can be straight chain or branched and is preferably a propargyl-, 2-butinyl-, 3-butinyl-, 4-pentinyl-, 5-hexinyl- or 4-methyl-2-pentinyl group,
- alkinylene is for example propenylene, butenylene, pentenylene, hexenylene, heptenylene, octenylene, nonenylene or decenylene,
- C3-C8-cycloalkyl is preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl,
-
- C1-C6-hydroxyalkyl contains a hydroxyl group in one of the above-named C1-C6-alkyl residues, especially in the form of the hydroxymethyl- and hydroxyethyl group, wherein
- C1-C6-alkoxy, C3-C6-alkenyloxy, C3-C6-alkinyloxy each contain, aside from the oxygen atom, one of the C1-C6-alkyl-, C3-C6-alkenyl- and/or C3-C6-alkinyl groups named above and the methoxy-, ethoxy-, isopropoxy, tert-butoxy-, allyloxy- and propargyloxy group are preferred and is to be understood as among C1-C6-alkoxy entirely or partially substituted with fluorine, for example difluoromethoxy, trifluoromethoxy or 2,2,2-trifluoroethoxy,
- C1-C6-alkylthio, C3-C6-alkenylthio, C3-C6-alkinylthio each contain, aside from the sulfur atom, one of the C1-C6-alkyl-, C3-C6-alkenyl- or C3-C6-alkinyl group named above, especially the methylthio-, ethylthio-, isopropylthio- and tert-butylthio groups,
- C3-C8cycloalkyloxy and C3-C8-cycloalkylthio are preferred as cyclopentyloxy- and cyclopentylthio- and/or cyclohexyloxy- and cyclohexylthio groups,
- C1-C7-alkanoyloxy groups contain, aside from the oxygen atom, an aliphatic acyl residue with 1 to 7 carbon atoms, especially the acetoxy-, propionyloxy- and pivaloyloxy group,
- C2-C7-alkoxycarbonyl groups contain, aside from the carbonyl group, one of the C1-C6-alkoxy groups mentioned above, especially the methoxycarbonyl-, ethoxycarbonyl-, isopropoxycarbonyl-, isobutoxycarbonyl- and tert-butoxycarbonyl group,
- C2-C7-alkoxycarbonyloxy groups contain, aside from the oxygen atom, one of the C2-C7-alkoxycarbonyl residues mentioned above, especially the methoxycarbonyloxy-, ethoxycarbonyloxy-, isopropoxycarbonyloxy-, isobutoxycarbonyloxy- and tert-butoxycarbonyl group as well as the allyloxycarbonyloxy group,
- C2-C7-alkylaminocarbonyl and C3-C13-dialkylaminocarbonyl groups contain, beside the carbonyl group, an alkylamino- and/or dialkylamino residue, whose C1-C6-alkyl groups have the above meanings, wherein the dimethylaminocarbonyl-, diethylaminocarbonyl- and the diisopropylaminocarbonyl groups are preferred, and aside from the unsubstituted amino group, one of the following C1-C6-alkylamino groups and/or di-(C1-C6-alkyl)amino groups are to be understood under the amino groups of the formula NR5R6,
- C1-C6-alkylamino contains one of the C1-C6-alkyl groups mentioned above, especially in form of the methylamino-, ethylamino-, propylamino-, isopropylamino-, butylamino- and the tert-butylamino group,
- di-(C1-C6-alkyl)amino carries two of the same or different of the above named C1-C6-alkyl groups on the nitrogen atom, especially in form of the dimethylamino-, diethylamino-, dipropylamino-, diisopropylamino-, isopropylmethylamino-, dibutylamino- or tert-butylmethylamino group,
- C1-C6-acyl is the residue of an aliphatic saturated or unsaturated, straight chain, branched or cyclic carboxylic acid, especially in form of the formyl-, acetyl-, propionyl-, acryloyl-, butyryl-, isobutyryl-, methacryloyl-, cyclopropylcarbonyl-, pentanoyl-, pivaloyl-, cyclobutylcarbonyl-, hexanoyl- and the dimethylacryloyl group,
- C1-C6-alkansulfonyl is preferably the methanesulfonyl-, ethanesulfonyl-, propanesulfonyl-, butanesulfonyl-, pentanesulfonyl- and the hexanesulfonyl group,
- saturated five- to seven-membered heterocycles with one or two hetero-atoms are especially tetrahydrofuryl, tetrahydrothienyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, hexahydroazepinyl, piperazinyl, hexahydrodiazepinyl or morpholinyl,
- monocyclic aromatic five- or six-membered heterocycles with one to three hetero-atoms are especially furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl or triazinyl,
- anellated bi- and tricyclic aromatic or partially hydrated carbocycle ring systems with 8 to 16 ring atoms and at least one aromatic are preferably benzocyclobutyl, indanyl, indenyl, naphthyl, dihydronaphthyl, tetrahydronaphthyl, biphenylenyl, fluorenyl, anthryl, dihydroanthryl, phenanthryl, dihydrophenanthryl, dibenzocycloheptenyl, dihydrodibenzocycloheptenyl, dihydrodibenzocyclooctenyl or tetrahydrodibenzocyclooctenyl, wherein mono- or dioxo-derivates, wherein the residues of indanone, tetralone, anthrone, anthraquinone, fluorenone, phenanthrone, dibezocycloheptenone, dihydrodibenzocycloheptenone or tetrahydrodibenzocyclootenone are for example also to be understood as partially hydrated carbocyclic ring systems,
- anellated bi- and tricyclic aromatic or partially hydrated heterocyclic ring systems with 8 to 16 ring atoms and at least one aromatic ring are, for example, imidazothiazolyl, benzofuryl, dihydrobenzofuryl, benzothienyl, dihydrobenzothienyl, indolyl, indolinyl, benzimidazolyl, indazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzofurazanyl, benzothiadiazolyl, benzotriazolyl, oxazolopyridyl, thiazolopyridyl, isothiazolopyridyl, imidazopyridyl, pyrazolopyridyl, thienopyrimidinyl, chromanyl, benzopyranyl, quinolyl, isoquinolyl, dihydroquinolyl, tetrahydroquinolyl, benzodioxanyl, quinoxalinyl, quinazolinyl, naphthyridinyl, carbazolyl, tetrahydrocarbazolyl, pyridoindolyl, acridinyl, phenothiazinyl, dihydrodibenzoxepinyl, benzocycloheptathienyl, dihydrothienobenzothiepinyl, dihydrodibenzothiepinyl, octahydrodibenzothiepinyl, dihydrodibenzazepinyl, octahydrodibenzazepinyl, benzocycloheptapyridyl, dihydropyridobenzodiazepinyl, dihydrodibenzoxazepinyl, dihydropyridobenzoxepinyl, dihydropyridobenzoxazepinyl, dihydrodibenzothiazepinyl or dihydropyridobenzothiazepinyl, wherein their mono- or dioxo-derivates and/or optionally their possible tautomeres are also to be understood as partially hydrated heterocyclic ring systems, for example, the residues of indolinone, isatin, benzoxazolone and/or its tautomeres hydroxybenzoxazol, of benzisoxazolone, benzothiazolone, benzoisothiazolone and benzimidazolone and/or their tautomeres, hydroxybenzisoxazol, hydroxybenzothiazol, hydroxybenzoisothiazol and hydroxybenzimidazol, of indazolinone, of oxazolopyridinone, thiazolopyridinones, pyrazolopyridinones and imidazopyridinones and/or their tautomeres hydroxyoxazolopyridine, hydroxythiazolopyridines, hydroxypyrazolopyridines and hydroxyimidazopyridines, the residues of chromanone, chromone, quinolinone, dihydroquinolinone, tetrahydrocarbazolone, acridone, of dihydrodibenzoxepinones, benzocycloheptathiophenones, dihydrothienobenzothiepinones, dihydrodibenzothiepinones, dihydrodibenzoazepinones, benzocycloheptapyridinones, dihydropyrido-benzoxazepinones, dihydrodibenzothiazepinones and of dihydropyridobenzothiazepinones,
- saturated and unsaturated monocyclic, four- to eight-membered heterocycles represent —NR12R14 as a grouping which, aside from the essential nitrogen atom, can optionally contain one or two further hetero-atoms selected from N and/or S and/or O, for example azetidine, pyrrolidine, piperidine, (1H)tetrahydropyridine, hexahydroazepine, (1H)tetrahydroazepine, octahydroazocine, pyrazolidine, piperazine, hexahydrodiazepine, morpholine, hexahydrooxazepine, thiomorpholine or thiomorpholine-1,1-dioxide,
- saturated or unsaturated bi- or tricyclic, anellated or bridged heterocycles with 8 to 16 ring atoms, represent —NR12R14 as a grouping which, aside from the essential nitrogen atom optionally contain one or two further hetero-atoms, selected from N and/or S and/or O, for example 5-aza-bicyclo[2.1.1]hexane, 2-aza-bicyclo[2.2.1]heptane, 7-aza-bicyclo[2.2.1]heptane, 2,5-diaza-bicyclo[2.2.1]heptane, 2-aza-bicyclo[2.2.2]octane, 8-aza-bicyclo[3.2.1]octane, 2,5-diaza-bicyclo[2.2.2]octane, 9-aza-bicyclo[3.3.1]nonane, indoline, isoindoline, (1H)-dihydroquinoline, (1H)-tetrahydroquinoline, (2H)-tetrahydroisoquinoline, (1H)-tetrahydroquinoxaline, (4H)-dihydrobenzoxazine, (4H)-dihydrobenothiazine, (1H) tetrahydrobenzo[b]azepine, (1H)-tetrahydrobenzo[c]azepine, (1H)-tetrahydrobenzo[d]azepine, (5H)-tetrahydrobenzo[b]oxazepine, (5H)-tetrahydrobenzothiazepine, 1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indol, (10H)-dihydroacridine, 1,2,3,4-tetrahydroacridanone, (10H)-phenoxazin, (10H)-phenothiazine, (5H)-dibenzazepine, (5H)-dihydrodibenzazepine, (5H)-octahydrodibenzazepine, (5H)-dihydrodibenzodiazepine, (11H)-dihydrodibenzo[b,e]oxazepine, (11H)-dihydrodibenzo[b,e]thiazepine, (10H)-dihydrodibenzo[b,f]oxazepine, (10H)-dihydrodibenzo[b,f]thiazepine or (5H)-tetrahydrodibenzazocine, as well as typical
- tautomeres in the case of substitution of the heterocycle as such or in an anellated ring system by free hydroxy-, mercapto- and/or amino group, and
- stereoisomers such as, if applicable, cis/trans-isomers, endo/exo-isomers, optic isomers such as enantiomers, diasteromers as pure isomers or mixtures and/or racemic mixtures as well as the pharmacologically acceptable acid addition salts with inorganic or organic acids, wherein the hydrochlorides, hydrobromides, hydroiodides, sulfates and phosphates, are preferred as addition salts with suitable inorganic acids and acetates, benzoates, citrates, fumarates, gluconates, malates, maleates, methanesulfonates, lactates, oxalates, succinates, tartrates and tosylates are preferred as addition salts of organic acids.
-
- have the following meanings, are especially preferred:
- R1 is hydrogen, halogen, cyano, C1-C6-alkyl, trifluoromethyl, C3-C8-cycloalkyl, C1-C4-hydroxyalkyl, hydroxy, C1-C4-alkoxy, benzyloxy, C1-C4-alkanoyloxy, C1-C4-alkylthio, C2-C8-alkoxycarbonyl, aminocarbonyl, C3-C9-dialkylaminocarbonyl, carboxy, phenyl, phenoxy, pyridyloxy or NR5R6, wherein
- R5 and
- R6 are selected independently from each other form hydrogen and C1-C6-alkyl,
- R2 is hydrogen, halogen, C1-C6-alkyl, trifluoromethyl or hydroxy, wherein
- R1 and R2, in the case they are adjacent, optionally form a bridge which are selected from the group of bridge members —(CH2)4— and —(CH═CH)2— and —CH2O—CR7R8—O—, wherein
- R7 and
- R8 can be, independently from each other, hydrogen and C1-C6-alkyl,
- R3 is selected from hydrogen, halogen and C1-C6-alkyl and
- R4 is selected from hydrogen, C1-C6-alkyl, C3-C6-alkenyl, hydroxy, C1-C6-alkoxy and benzyloxy,
- k is 0 or 1,
- A is C2-C6-alkenylene, which is optionally substituted one to three-fold by C1-C3-alkyl, hydroxy, fluorine, cyano, or phenyl,
- C4-C6-alkadienylene, which is optionally substituted once or twice by C1-C3-alkyl, fluorine, cyano, or phenyl,
- 1,3,5-hexatrienylene, which is optionally substituted by C1-C3-alkyl, fluorine, or cyano, as well as
- ethinylene
- D is selected from C1-C10-alkylene, which is optionally substituted once or twice by C1-C3-alkyl or hydroxy,
- C2-C10-alkenylene, optionally substituted once or twice by C1-C3-alkyl or hydroxy, wherein the double bond can also be to ring E or
- C3-C10-alkinylene, which is optionally substituted once or twice by C1-C3-alkyl or hydroxy, and can be selected as well from
- C1-C10-alkylene, C2-C10-alkenylene or C3-C10-alkinylene, in which one to three methylene units are isosterically replaced by O, S, NR9, CO, SO or SO2, wherein
- R9 is hydrogen, C1-C3-alkyl, C1-C6-acyl or metanesulfonyl,
- E is
- wherein the heterocyclic ring can optionally have a double bond and
- n and p can be, independent of each other, 0, 1, 2 or 3, with the proviso that n+p≦4,
- q is 2 or 3,
- R10 is selected from hydrogen, C1-C3-alkyl, hydroxy, hydroxymethyl, carboxy or C2-C7-alkoxycarbonyl and
- R11 is selected from hydrogen or an oxo group adjacent to the nitrogen atom,
- G is selected from hydrogen,
- G1, G2, G3, G4 and G5, wherein
- G1 represents the residue
—(CH2)r—(CR13R14)s—R12 (G1)- wherein
- r is 0, 1 or 2 and
- s is 0 or 1,
- R12 is selected from hydrogen, C1-C6-alkyl, C3-C6-alkenyl C3-C8-alkinyl, C3-C8-cycloalkyl,
- benzyl, phenyl,
- monocyclic aromatic five- or six-membered heterocycles, which contain one to the hetero-atoms from the group N and/or S and/or O and we either bound directly or over a methylene group,
- anellated bi- and tricyclic aromatic or partially hydrated carbocyclic ring systems with 8 to 16 ring atoms and at least one aromatic ring, whereby the bond can occur either over an aromatic or a hydrated ring and either directly or over a methylene group,
- anellated bi- and tricyclic aromatic or partially hydrated heterocyclic ring systems with 8 to 16 ring atoms and at least one aromatic ring, wherein one to three ring atoms can be selected from the groups N and/or S and/or O and the bond can occur either over an aromatic or a hydrated ring and either directly or over a methylene group,
- R13 has the same meaning as R12, but is selected independently thereof,
- R14 is selected from hydrogen, hydroxy, methyl, benzyl or phenyl,
- monocyclic aromatic five- or six-membered heterocycles, which can contain one to three hetero-atoms selected from the group N and/or S and/or O and are bound either directly or over a methylene group,
- anellated bi- and tricyclic aromatic or partially hydrated carbocyclic ring systems with 8 to 16 ring atoms and at least einem aromatic ring, wherein the bond can occur either over an aromatic or a hydrated ring and either directly or over a methylene group,
- anellated bi- and tricyclic aromatic or partially hydrated heterocyclic ring system with 8 to 16 ring atoms and at least one aromatic ring, wherein one to three ring atoms can be selected from the group N and/or S and/or O and the bond can occur either over an aromatic or a hydrated ring and either directly or over a methylene group,
- G2 is selected from the residues
- wherein the substituents R12 and R14 the can have the above meaning, or the grouping
—NR12R14 - can also be a nitrogen heterocycle bound over the nitrogen atom, selected from
- saturated or unsaturated monocyclic, four- to eight-membered heterocycles, which, aside from the essential nitrogen atom, can optionally contain one or two further hetero-atoms selected from N and/or S and/or O, or
- saturated or unsaturated bi- or tricyclic, anellated or bridged heterocycles with 8 to 16 ring atoms, which, aside from the essential nitrogen atom, can optionally contain one or two further hetero-atoms selected from N and/or S and/or O,
- wherein the substituents R12 and R14 the can have the above meaning, or the grouping
- G3 is the residue
—SO2—(CH2)rR12 (G3), - G4 is the residue
- wherein
- Ar1 and
- Ar2 are selected independently of each other from phenyl, pyridyl or naphthyl,
- G5 is the residue
—COR15 (G5)- wherein
- R15 is trifluoromethyl, C1-C6-alkoxy, C3-C6-alkenyloxy or benzyloxy and
- aromatic ring systems in which the substituents R1, R2, R4, R12R13, R14, R15, Ar1 and Ar2 and/or in the ring system —NR12R14 can carry independently of each other one to three of the same or different substituents from the series halogen, cyano, C1-C6-alkyl, trifluoromethyl, C3-C8-cycloalkyl, phenyl, benzyl, hydroxy, C1-C6-alkoxy, which can be optionally entirely or partially substituted by fluorine, benzyloxy, phenoxy, mercapto, C1-C6-alkylthio, carboxy, C1-C6-alkoxycarbonyl, benzyloxycarbonyl, nitro, amino, mono-C1-C6-alkylamino, di-(C1-C6-alkyl)-amino, wherein two adjacent groups on the aromatic ring or ring system can form an additional ring over a methylenedioxy bridge.
-
- have the following meanings are particularly preferred:
- R1 is hydrogen, halogen, cyano, methyl, trifluoromethyl, hydroxy, C1-C4-alkoxy, ethylthio, methoxycarbonyl, tert-butoxycarbonyl, aminocarbonyl, carboxy, and phenoxy,
- R2 is hydrogen, halogen, trifluoromethyl or hydroxy,
- R3 is hydrogen or halogen,
- R4 is selected from hydrogen, C1-C3-alkyl, hydroxy and C1-C3-alkoxy,
- k is 0 or 1,
- A is C2-C6-alkenylene, which is optionally substituted once or twice by C1-C3-alkyl, hydroxy or fluorine, or
- C4-C6-alkadienylene, which is optionally substituted by is C1-C3-alkyl or by 1 or 2 fluorine atoms, or
- 1,3,5-hexatrienylene, which is optionally substituted by fluorine, as well as
- D is C1-C8-alkylene, which is optionally substituted once twice by methyl or hydroxy,
- C2-C8-alkenylene, which is optionally substituted once or twice by methyl or hydroxy, wherein the double bond can also be to ring E,
- C3-C8-alkylene, which is optionally substituted once or twice by methyl or hydroxy, as well as
- C1-C9-alkylene, C2-C8-alkenylene, or C3-C8-alkinylene, in which one to three methylene units can be isosterically replaced by O, S, NH, N(CH3), N(COCH3), N(SO2CH3), CO, SO or SO2,
- E is
- wherein the heterocyclic ring can optionally have a double bond and
- n and
- p can be independent of each other 0, 1, 2 or 3, with the proviso that n+p≦3,
- q is 2 or 3,
- R10 is selected from hydrogen, C1-C3-alkyl, hydroxy, hydroxymethyl and
- R11 is selected from hydrogen or an oxo group which is adjacent to the nitrogen atom,
- G is hydrogen or
- G1, G2, G3, G4 and G5, wherein
- G1 represents the residue
—(CH2—)(CR13R14)s—R12 (G1)- wherein
- r is 0, 1 or 2 and
- s is 0 or 1,
- R12 is selected from hydrogen, C1-C6-alkyl, C3-C8-cycloalkyl, benzyl or phenyl,
- benzocyclobutyl, indanyl, indenyl, oxoindanyl, naphthyl, dihydronaphthyl, tetrahydronaphthyl, oxotetrahydronaphthyl, biphenylenyl, fluorenyl, oxofluorenyl, anthryl, dihydroanthryl, oxodihydroanthryl, dioxodihydroanthryl, phenanthryl, dihydrophenanthryl, oxodihydrophenanthryl, dibenzocycloheptenyl, oxodibenzocycloheptenyl, dihydrodibenzocycloheptenyl oxodihydrodibenzocycloheptenyl, dihydrodibenzocyclooctenyl, tetrahydrodibenzocyclooctenyl and oxotetrahydrodibenzocyclooctenyl, bound directly or over a methylene group, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, triazinyl, imidazothiazolyl, benzofuryl, dihydrobenzofuryl, benzothienyl, dihydrobenzothienyl, indolyl, indolinyl, oxoindolinyl, dioxoindolinyl, benzoxazotyl, oxobenzoxazolinyl, benzisoxazolyl, oxobenzisoxazolinyl, benzothiazolyl, oxobenzthiazolinyl, benzisothiazolyl, oxobenzoisothiazolinyl, benzimidazolyl, oxobenzimidazolinyl, indazolyl, oxoindazolinyl, benzofurazanyl, benzothiadiazolyl, benzotriazolyl, oxazolopyridyl, oxodihydrooxazolopyridyl, thiazolopyridyl, oxodihydrothiazolopyridyl, isothiazolopyridyl, imidazopyridyl, oxodihydroimidazopyridyl, pyrazolopyridyl, oxodihydropyrazolopyridyl, thienopyrimidinyl, chromanyl, chromonyl, benzopyranyl, chromonyl, quinolyl, isoquinolyl, dihydroquinolyl, oxodihydroquinolinyl, tetrahydroquinolyl, oxotethydroquinolinyl, benzodioxanyl, quinoxalinyl, quinolinyl, naphthyridinyl, carbazolyl, tetrahydrocarbazolyl, oxotetrahydrocarbazolyl, pyridoindolyl, acridinyl, oxodihydroacidinyl, phenothiazinyl, dihydrodibenzoxepinyl, oxodihydrodibenzoxepinyl, benzocycloheptathienyl, oxobenzocycloheptathienyl, dihydrothienobenzothiepinyl, oxodihydrothienobenzothiepinyl dihydrodibenzothiepinyl, oxodihydrodibenzothiepinyl, octahydrodibenzothiepinyl, dihydrodibenzazepinyl, oxodihydrodibenzazepinyl, octahydrodibenzazepinyl, benzocycloheptapyridyl, oxobenzocycloheptapyridyl, dihydropyridobenzodiazepinyl, dihydrodibenzoxazepinyl, dihydropyridobenzoxepinyl, dihydropyridobenzoxazepinyl, oxodihydropyridobenzoxazepinyl, dihydrodibenzothiazepinyl, oxodihydrodibenzothiazepinyl, dihydropyridobenzothiazepinyl, oxodihydropyridobenzothiazepinyl, bound directly or over a methylene group,
- R13 has the same meaning as R12, but is selected independently therefrom,
- R14 is selected from hydrogen, hydroxy, methyl, benzyl or phenyl,
- indanyl, indenyl, naphthyl, dihydronaphthyl, tetrahydronaphthyl, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, triazinyl, benzofuryl, benzothienyl, indolyl indolinyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, chromanyl, quinolyl or tetrahydroquinolyl bound directly or over a methylene group,
- G2 is selected from the residues
- wherein the substituents R17 and R14 can have the above meanings, or represents the grouping
—NR12R14 - over the nitrogen-bound ring atom of azetidine, pyrrolidine, piperidine, (1H)tetrahydropyridine, hexahydroazepine, (1H)tetrahydroazepine, octahydroazocine, pyrazolidine, piperazine, hexyhydrodiazepine, morpholine, hexahydrooxazepine, thiomorpholine, thiomorpholine-1,1-dioxide, 5-aza-bicyclo[2.1.1]hexane, 2-aza-bicyclo[2.2.1]heptane, 7-aza-bicyclo[2.2.1]heptane, 2,5-diaza-bicyclo[2.2.1]heptane, 2-aza-bicyclo[2.2.2]octane, 8-aza-bicyclo[3.2.1]octane, 2,5-diazabicylo[2.2.2]octane, 9-azabicyclo[3.3.1]nonane, indoine, isoindoline, (1H)-dihydroquinoline, (1H)-tetrahydroquinoline, (2H)-tetrahydroisoquinoline, (1H)-tetrahydroquinoxalin, (4H)-dihydrobenzoxazine, (4H)-dihydrobenzothiazine, (1H)-tetrahydrobenzo[b]azepine, (1H)-tetrahydrobenzo[c]azepine, (1H)-tetrahydrobenzo[d]azepine, (5H)-tetrahydrobenzo[b]oxazepine, (5H)-tetrahydrobenzo[b]thiazepine, 1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole, (10H)dihydroacridine, 1,2,3,4-tetrahydroacridanone, (10H)-phenoxazine, (10H)-phenothiazine, (5H)-dibenzazepine, (5H)-dihydrodibenzazepine, (5H)-Octahydrodibenzazepine, (5H)-dihydrodibenzodiazepine, (11H)-dihydrodibenzo[b,e]oxazepine, (11H)-dihydrodibenzo[b,e]thiazepine, (10H)-dihydrodibenzo[f]oxazepine, (10H)-dihydrodibenzo[b,f]thiazepine or (5H)-tetrahydrodibenzazocine,
- wherein the substituents R17 and R14 can have the above meanings, or represents the grouping
- G3 is the residue
—SO2—(CH2)rR12 (G3), - G4 is the residue
- wherein
- Ar1 and
- Ar2 are selected independently of each other from phenyl, pyridyl or naphthyl,
- G5 is the residue
—COR15 (G5)- wherein
- R15 is trifluoromethyl C1-C6-alkoxy, C3-C6-alkenyloxy or benzyloxy and
- aromatic ring systems in which the substituents can be substituted independently of each other by one to three of the same or different substituents from the series halogen, cyano, C1-C6-alkyl, trifluoromethyl, C3-C8-Cycloalkyl, phenyl, benzyl, hydroxy, C1-C6-alkoxy, C1-C6-alkoxy, which can be entirely or partially substituted by fluorine, can carry benzyloxy, phenoxy, mercapto, C1-C6-alkylthio, carboxy, C1-C6-alkoxycarbonyl, benzyloxycarbonyl, nitro, amino, mono-C1-C6-alkylamino, di-(C1-C6-alkyl)-amino, wherein two adjacent groups can form an additional ring with a methylenedioxy bridge.
-
- have the following meaning:
- R1 is hydrogen, halogen, cyano, methyl, trifluoromethyl, hydroxy, methoxy or methoxycarbonyl,
- R2 is hydrogen or halogen,
- R3 is hydrogen,
- R4 is selected from hydrogen, C1-C3-alkyl or hydroxy,
- k is 0 or 1,
- A is selected from C2-C6-alkylene, which is optionally substituted once or twice by hydroxy or fluorine, or
- C2-C6-alkenylene, which is optional substituted once or twice by hydroxy or fluorine,
- C4-C6-alkadienylene, which is optionally substituted by 1 or 2 fluorine atoms, or
- 1,3,5-hexatrienylene,
- D is C2-C8-alkylene, which is optionally substituted by methyl or hydroxy,
- C2-C8-alkenylene, which is optionally substituted by methyl or hydroxy, wherein the double bond can also be to ring E, or
- C2-C8-alkylene, C2-C8-alkenylene, wherein one to three methylene units can be isosterically replaced by O, NH, N(CH3), N(COCH3), N(SO2CH3) or CO,
- E is selected from the residues
- wherein the heterocyclic ring can optionally have a double bond and
- n and p can be, independent of each other, 0, 1, 2 or 3, with the proviso that n+p≦3 and
- q is 2
- R10 is hydrogen, methyl or hydroxyl and
- R11 is hydrogen or an oxo group adjacent to the nitrogen atom,
- G is selected from hydrogen, C3-C8-cycloalkyl, methoxycarbonyl, tertbutoxycarbonyl, benzyloxycarbonyl, trifluoroacetyl, diphenylphosphinoyl or the residues
- wherein
- r is 0, 1 or 2 and
- s is 0 or 1,
- R12 is hydrogen, methyl, benzyl or phenyl,
- indanyl, indenyl, oxoindanyl, naphthyl, dihydronaphthyl, tetrahydronaphthyl, oxotetrahydronaphthyl, fluorenyl, oxofluorenyl, anthryl, dihydroanthryl, oxodihydroanthryl, dioxodihydroanthryl, dibenzocycloheptenyl, oxodibenzocycloheptenyl, dihydrodibenzocycloheptenyl, oxodihydrodibenzocycloheptenyl bound directly or over a methylene group,
- furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl pyrazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, imidazothiazolyl, benzofuryl, dihydrobenzofuryl, benzothienyl, dihydrobenzothienyl, indolyl, indolinyl, oxoindolinyl, dioxoindolinyl, benzoxazolyl, oxobenzoxazolinyl, benzisoxazolyl, oxobenzisoxazolinyl, benzothiazolyl, oxobenzthiazolinyl, benzoisothiazolyl, oxobenzoisothiazolinyl, benzimidazolyl, oxobenzimidazolinyl, benzofurazanyl, benzothiadiazolyl, benzotriazolyl, oxazolopyridyl, oxodihydrooxazolopyridyl, thiazolopyridyl, oxodihydrothiazolopyridyl, isothiazolopyridyl, imidazopyridyl oxodihydroimidazopyridyl, pyrazolopyridyl, thienopyrimidinyl, chromanyl, chromanonyl, benzopyranyl, chromonyl, quinolyl, isoquinolyl, dihydroquinolyl, oxodihydroquinolinyl, tetrahydroquinolyl, oxotetrahydroquinolinyl, benzodioxanyl, quinoxalinyl, quinazolinyl, naphthyridinyl, carbazolyl, tetrahydrocarbazolyl, oxotetrahydrocarbazolyl, pyridoindolyl, acridinyl, oxodihydroacridinyl, phenothiazinyl, dihydrodibenzoxepinyl, benzocycloheptathienyl, oxobenzocycloheptathienyl, dihydrothienobenzothiepinyl, oxodihydrothienobenzothiepinyl dihydrodibenzothiepinyl, oxodihydrodibenzothiepinyl, dihydrodibenzazepinyl, oxodihydrodibenzazepinyl, octahydrodibenzazepinyl, benzocycloheptapyridyl, oxobenzocycloheptapyridyl, dihydropyridobenzoxepinyl, dihydrodibenzothiazepinyl, oxodihydrodibenzothiazepinyl bound directly or over a methylene group,
- R13 is hydrogen, methyl, benzyl or phenyl,
- R14 is selected from hydrogen, hydroxy, methyl, benzyl, phenyl,
- naphthyl, furyl, thienyl, oxazolyl, thiazolyl, pyrazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyridyl, benzofuryl, benzothienyl, indolyl, indolinyl benzoxazolyl, benzothiazolyl, benzimidazolyl, chromanyl, quinolyl or tetrahydroquinolyl, bound directly or over a methylene group, wherein in formula (I)
- —NR12R14 can also be selected from pyrrolidine, piperidine, (1H)tetrahydropyridine, hexahydroazepine, Octahydroazocine, piperazine, hexahydrodiazepine, morpholine, hexahydrooxazepine, 2-azabicyclo[2.2.1]heptane, 7-azabicyclo[2.2.1]heptane, 2,5-diazabicyclo[2.2.1]heptane, 8-azabicyclo[3.2.1]octane, 2,5-diazabicyclo[2.2.2]octane, indoline, isoindoline, (1H)-dihydroquinoline, (1H)-tetrahydroquinoline, (2H)-tetrahydroisoquinoline, (1H)-tetrahydroquinoxaline, (4H)-dihydrobenzoxazine, (4H)-dihydrobenzothiazine, (1H)-tetrahydrobenzo[b]azepine, (1H)-tetrahydrobenzo[d]azepine, (5H)-tetrahydrobenzo[b]oxazepine, (5H)-tetrahydrobenzo[b]thiazepine, 1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indol, (10H)-dihydroacridine, 1,2,3,4-tetrahydroacridanone, (5H)-dihydrodibenzazepine, (5H)-dihydrodibenzodiazepine, (11H)-dihydrodibenzo[b,e]oxazepine, (11H)-dihydrodibenzo[b,e]thiazepine, (10H)-dihydrodibenzo[b,f]oxaze-pine or (5H)-tetrahydrodibenzazocine.
- naphthyl, furyl, thienyl, oxazolyl, thiazolyl, pyrazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyridyl, benzofuryl, benzothienyl, indolyl, indolinyl benzoxazolyl, benzothiazolyl, benzimidazolyl, chromanyl, quinolyl or tetrahydroquinolyl, bound directly or over a methylene group, wherein in formula (I)
-
- have the following meanings are very particularly preferred:
- R1 is hydrogen, fluorine, chlorine, bromine, methyl, trifluoromethyl or hydroxy,
- R2 and
- R3 are hydrogen,
- R4 is hydrogen or hydroxy,
- k is 0 or 1,
- A is selected from C2-C4-alkylene, which is optionally substituted by fluorine,
- D is selected from C2-C6-alkylene, C2-C6-alkenylene, wherein the double bond can also be to ring E, and C2-C6-alkylene and C2-C6-alkenylene, wherein a methylene unit can be isosterically replaced by O, NH, N(CH3) or CO or an ethylene group can be isosterically replaced by NH—CO and/or CO—NH or a propylene group can be isosterically replaced by NH—O and/or O—CO—NH,
- E is selected from pyrrolidine, piperidine, 1,2,5,6-tetrahydropyridine, hexahydroazepine, morpholine and hexahydro-1,4-oxazepine, wherein the heterocyclic ring optionally adjacent to the nitrogen atom, can be substituted by an oxo group,
- G is selected from hydrogen, tert-butoxycarbonyl, diphenylphosphinoyl, or one of the residues
- wherein
- r is 0 or 1 and
- s is 0 or 1,
- R12 is hydrogen methyl, benzyl or phenyl,
- indenyl, oxoindanyl, naphthyl tetrahydronaphthyl, fluorenyl, oxofluorenyl, anthryl, dihydroanthryl, oxodihydroanthryl, dioxodihydroanthryl, dibenzocycloheptenyl, dihydrodibenzocycloheptenyl bound directly or over a methylene group,
- furyl, thienyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, imidazothiazolyl, benzofuryl, benzothienyl, indolyl, oxoindolinyl, dioxoindolinyl, benzoxazolyl, oxobenzoxazolinyl, benzothiazolyl, oxobenzthiazolinyl, benzimidazolyl, oxobenzimidazolinyl, benzofurazanyl, benzotriazolyl, oxazolopyridyl, oxodihydrooxazolopyridyl, thiazolopyridyl, oxodihydrothiazolopyridyl, chromanyl, chromanonyl, benzopyranyl, chromonyl, quinolyl, isoquinolyl, oxodihydroquinolinyl, tetrahydroquinolyl, oxotetrahydroquinolinyl, benzodioxanyl, quinazolinyl, acridinyl, oxodihydroacridinyl, phenothiazinyl, dihydrodibenzoxepinyl, benzocycloheptathienyl, dihydrothienobenzothiepinyl, dihydrodibenzothiepinyl, oxodihydrodibenzothiepinyl, dihydrodibenzazepinyl, oxodihydrodibenzazepinyl, octahydrodibenzazepinyl, benzocycloheptapyridyl, oxobenzocycloheptapyridyl, dihydrodibenzothiazepinyl bound directly or over a methylene group,
- R13 is hydrogen, methyl, benzyl or phenyl,
- R14 is hydrogen, hydroxy, methyl, benzyl or phenyl,
- naphthyl, furyl thienyl, pyridyl, benzofuryl, benzothienyl, indolyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, chromanyl, quinolyl or tetrahydroquinolyl bound directly or over a methylene group, wherein in the formula
- —NR12R14 can be selected from pyrrolidine, piperidine, hexahydroazepine, morpholine, 2,5-diazabicyclo[2.2.1]heptane, indoline, isoindoline, (1H)-dihydroquinoline, (1H)-tetrahydroquinoline, (2H)-tetrahydroisoquinoline, (1H)-tetrahydrobenzo[b]azepine, (1H)-tetrahydrobenzo[d]azepine, (5H)-tetrahydrobenzo[b]oxazepine, (5H)-tetrahydrobenzo[b]thiazepine, 1,2,3,4-tetrahydroacridanone, (5H)-dihydrodibenzazepine, (11H)-dihydrodibenzo[b,e]-oxazepine or (11H)-dihydrodibenzo[b,e]thiazepine and
- wherein aromatic ring systems in the substituents can be substituted, independently of each other, by one to three of the same or different substituents from the series halogen, cyano, C1-C6-alkyl, trifluoromethyl, C3-C8-cycloalkyl, phenyl, benzyl, hydroxy, C1-C6-alkoxy, C1-C6-alkoxy, which can be entirely or partially substituted by fluorine, can carry benzyloxy, phenoxy, mercapto, C1-C6-alkylthio, carboxy, C1-C6-alkoxycarbonyl, benzyloxycarbonyl, nitro, amino, mono-C1-C6-alkylamino or di-(C1-C6-alkyl)-amino, whereby two adjacent groups on the aromatic ring or ring system can form an additional ring over a methylenedioxy bridge.
- naphthyl, furyl thienyl, pyridyl, benzofuryl, benzothienyl, indolyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, chromanyl, quinolyl or tetrahydroquinolyl bound directly or over a methylene group, wherein in the formula
-
- have the following meanings:
- R1 is hydrogen, fluorine, methyl, trifluoromethyl or hydroxy,
- R2 and
- R3 are hydrogen,
- R4 is hydrogen or hydroxy,
- k is 0,
- A is ethenylene (vinylene) or 1,3-butadienylene,
- D is selected from C2-C6-alkylene, or C2-C6-alkenylene, wherein the double bond can also be to ring E,
- E is selected from pyrrolidine, piperidine, hexahydroazepine or morpholine,
- G is selected from benzyl, phenethyl, fluorenylmethyl, anthrylmethyl, diphenylmethyl, fluorenyl or dihydrodibenzocycloheptenyl,
- furylmethyl, thienylmethyl, thiazolylmethyl, pyridylmethyl, benzothienylmethyl, quinolylmethyl, phenyl-thienylmethyl, phenyl-pyridylmethyl, dihydrodibenzoxepinyl, dihydrodibenzothiepinyl,
- acetyl, pivaloyl, phenylacetyl, diphenylacetyl, diphenylpropionyl, naphthylacetyl, benzoyl, naphthoyl, anthrylcarbonyl, oxofluorenylcarbonyl, oxodihydroanthrylcarbonyl or dioxodihydroanthrylcarbonyl,
- furoyl, pyridylcarbonyl, chromonylcarbonyl, quinolylcarbonyl,
- naphthylaminocarbonyl, dibenzlaminocarbonyl, benzylphenylaminocarbonyl, diphenylaminocarbonyl, indolinyl-1-carbonyl, dihydrodibenzazepin-N-carbonyl, tetrahydroquinolinyl-N-carbonyl, tetrahydrobenzo[b]azepinyl-N-carbonyl, methanesulfonyl, phenylsulfonyl, p-toluenesulfonyl, naphthylsulfonyl, quinolinsulfonyl and
- diphenylphosphinoyl,
- wherein aromatic ring systems can be substituted independently of each other by one to three of the same or different substituents from the series halogen, cyano, C1-C6-alkyl, trifluoromethyl, C3-C8-cycloalkyl, phenyl, benzyl, hydroxy, C1-C6-alkoxy, C1-C6-alkoxy, which can be entirely or partially substituted by fluorine, benzyloxy, phenoxy, mercapto, C1-C6-alkylthio, carboxy, C1-C6-alkoxycarbonyl, benzyloxycarbonyl, nitro, amino, mono-C6-alkylamino or di-(C1-C6-alkyl)-amino, wherein two adjacent groups in the ring or ring system can form an additional ring over a methylenedioxy bridge.
- A series of exemplary compounds with the respective substituent definitions are listed in the following Table 1 for illusion of the invention without restricting the scope of the compounds according to the invention.
TABLE 1 Exemplfying compounds of formula (I) according to the invention Nr R1 k A R4 D—E—G 1 H 0 CH═CH H 2 H 0 CH═CH—CH═CH H 3 H 0 CH═CH H 4 H 0 CH═CH H 5 H 0 CH═CH H 6 H 0 CH═CH H 7 H 0 CH═CH—CH═CH H 8 H 0 CH═CH(CH2)2 H 9 H 0 CH═CH H 10 H 0 CH═CH H 11 H 0 CH═CH H 12 H 0 CH═CH H 13 H 0 CH═CH H 14 H 0 CH═CH H 15 H 0 CH═CH—CH═CH H 16 H 0 CH═CH H 17 H 0 CH═CH H 18 H 0 CH═CH—CH═CH H 19 H 0 CH═CH—CH═CH H 20 H 0 CH═CH(CH2)2 H 21 H 0 CH═CH H 22 H 0 H 23 H 0 CH═CH H 24 H 0 CH═CH H 25 H 0 CH═CH H 26 H 0 CH═CH H 27 H 0 CH═CH H 28 H 0 CH═CH h 29 H 0 CH═CH H 30 H 0 CH═CH—CH═CH H 31 H 1 CH═CH H 32 H 0 CH═CH OH 33 H 0 H 34 H 0 C≡C H 35 H 0 CH═CH(CH2)2 H 36 H 0 CH═CH—CH═CH H 37 2-F 0 CH═CH—CH═CH H 38 H 0 (CH═CH)3 H 39 H 0 CH═CH H 40 H 0 CH═CH H 41 H 0 CH═CH H 42 H 0 CH═CH H 43 H 0 CH═CH H 44 H 0 CH═CH H 45 H 0 CH═CH H 46 H 0 CH═CH—CH═CH H 47 H 0 CH═CH—CH═CH H 48 H 0 CH═CH—CH═CH H 49 H 0 CH═CH—CH═CH H 50 H 0 C≡C H 51 H 0 CH═CH H 52 H 0 CH═CH—CH═CH H 53 H 0 CH═CH H 54 H 0 CH═CH H 55 H 0 CH═CH—CH═CH H 56 H 1 CH═CH H 57 H 0 CH═CH(CH2)2 H 58 H 0 CH≡CHCH2CHF H 59 H 0 CH═CH H 60 H 0 CH═CH H 61 H 0 CH═CH—CH═CH H 62 H 0 CH═CH H 63 H 1 CH═CH H 64 H 0 CH═CH OH 65 H 0 H 66 H 0 C≡C H 67 H 0 CH═CH(CH2)2 H 68 H 0 H 69 H 0 (CH2)2CH═CH H 70 H 0 CH═CH—CH═CH H 71 H 0 CH═CH—CH═CH CH3 72 2-F 0 CH═CH—CH═CH H 73 2-F 0 CH═CH—CH═CH OH 74 4-F 0 CH═CH—CH═CH H 75 5-F 0 CH═CH—CH═CH H 76 6-F 0 CH═CH—CH═CH H 77 2-Cl 0 CH═CH—CH═CH H 78 6-CH3 0 CH═CH—CH═CH H 79 2-OH 0 CH═CH—CH═CH H 80 H 0 (CH═CH)3 H 81 H 0 CH═CH H 82 2-F 0 CH═CH H 83 5-F 0 CH═CH H 84 6-CH3O 0 CH═CH H 85 H 0 CH═CH—CH═CH H 86 H 0 CH═CH H 87 H 0 CH═CH—CH═CH H 88 H 0 CH═CH H 89 H 0 CH═CH H 90 H 0 CH═CH H 91 H 0 CH═CH H 92 H 0 CH═CH H 93 H 0 CH═CH—CH═CH H 94 H 0 CH═CH H 95 H 0 CH═CH—CH═CH H 96 H 0 CH═CH H 97 H 0 CH═CH H 98 H 0 CH═CH—CH═CH H 99 H 0 CH═CH H 100 H 0 CH═CH H 101 H 0 CH═CH H 102 H 0 CH═CH H 103 H 0 CH═CH H 104 H 0 CH═CH H 105 H 0 CH═CH H 106 H 0 CH═CH H 107 H 0 CH═CH H 108 H 0 CH═CH H 109 H 0 CH═CH—CH═CH H 110 H 0 C≡C H 111 H 0 CH═CH—CH═CH H 112 H 0 C≡C H 113 H 0 (CH2)2CH═CH H 114 H 0 CH═CH—CH═CH H 115 H 0 CH═CH—CH═CH H 116 H 0 CH═CH—CH═CH H 117 H 0 CH═CH—CH═CH H 118 H 0 CH═CH—CH═CH H 119 H 0 CH═CH H 120 H 0 CH═CH—CH═CH H 121 H 0 CH═CH H 122 H 0 CH═CH—CH═CH H 123 H 0 CH═CH H 124 H 0 CH═CH—CH═CH H 125 H 0 H 126 H 0 CH═CH—CH═CH H 127 H 0 CH═CHCH2CHF H 128 H 0 CH═CH—CH═CH H 129 H 0 C≡C H 130 H 0 CH═CH H 131 H 0 CH═CH—CH═CH H 132 H 0 CH═CH H 133 H 0 CH═CH H 134 H 0 CH═CH H 135 H 0 CH═CH—CH═CH H 136 H 0 CH═CH H 137 H 0 CH═CH—CH═CH H 138 H 0 CH═CH H 139 H 0 CH═CH—CH═CH H 140 H 0 CH═CH H 141 H 0 CH═CH—CH═CH H 142 H 0 CH═CH H 143 H 0 CH═CH H 144 H 0 CH═CH H 145 H 0 CH═CH—CH═CH H 146 H 0 CH═CH H 147 H 0 CH═CH H 148 H 0 CH═CH—CH═CH H 149 H 0 CH═CH(CH2)2 H 150 H 0 CH═CH H 151 H 0 CH═CH—CH═CH H 152 H 0 CH═CH H 153 H 0 CH═CH H 154 H 0 CH═CH—CH═CH H 155 H 0 CH═CH H 156 H 0 CH═CH H 157 H 0 CH═CH—CH═CH H 158 H 0 CH═CH H 159 H 0 CH═CH H 160 H 0 H 161 H 0 H 162 H 0 CH═CH—CH═CH H 163 H 0 CH═CH H 164 H 0 CH═CH CH3 165 H 0 CH═CH H 166 H 0 CH═CH H 167 H 0 CH═CH H 168 H 0 CH═CH—CH═CH H 169 H 0 CH═CH H 170 H 0 (CH2)2CH═CH H 171 H 0 CH═CH H 172 2-F 0 CH═CH H 173 H 0 CH═CH—CH═CH H 174 H 0 CH═CH H 175 H 0 CH═CH H 176 H 0 CH═CH—CH═CH H 177 H 0 CH═CH H 178 H 0 CH═CH H 179 H 0 CH═CH—CH═CH H 180 H 0 CH═CH H 181 H 0 CH═CH H 182 4-F 0 CH═CH H 183 H 0 CH═CH—CH═CH H 184 H 0 CH═CH H 185 H 0 CH═CH H 186 H 0 (CH═CH)3 H 187 H 0 CH═CH H 188 H 0 CH═CH—CH═CH H 189 H 0 CH═CH H 190 H 0 C≡C H 191 H 0 CH═CH H 192 H 0 CH═CH H 193 H 0 CH═CH H 194 H 0 CH═CH—CH═CH H 195 H 0 CH═CH H 196 2-Cl 0 CH═CH H 197 H 0 CH═CH H 198 H 0 CH═CH H 199 H 0 CH═CH H 200 H 0 CH═CH—CH═CH H 201 H 0 CH═CH H 202 H 0 CH═CH—CH═CH H 203 H 0 CH═CH H 204 H 0 CH═CH—CH═CH H 205 H 0 CH═CH H 206 H 0 CH═CH—CH═CH H 207 H 0 CH═CH H 208 H 0 CH═CH H 209 H 0 CH═CH—CH═CH H 210 H 0 CH═CH H 211 H 0 CH═CH H 212 H 0 CH═CH H 213 H 0 CH═CH H 214 H 0 CH═CH—CH═CH H 215 H 0 CH═CH H 216 H 0 CH═CH H 217 H 0 CH═CH H 218 H 0 CH═CH—CH═CH H 219 H 0 CH═CH H 220 H 0 C≡C H 221 H 0 (CH2)2CH═CH H 222 H 0 CH═CH—CH═CH H 223 H 0 CH═CH H 224 H 0 CH═CH H 225 H 0 CH═CH H 226 H 0 CH═CH—CH═CH H 227 H 0 CH═CH H 228 H 0 CH═CH H 229 H 0 CH═CH H 230 H 0 CH═CH—CH═CH H 231 H 0 CH═CH H 232 H 0 CH═CH H 233 H 0 CH═CH—CH═CH H 234 H 0 CH═CH H 235 H 0 CH═CH H 236 H 0 CH═CH—CH═CH H 237 H 0 CH═CH H 238 H 0 CH═CH—CH═CH H 239 H 0 CH═CH H 240 H 0 CH═CH H 241 H 0 CH═CH—CH═CH H 242 H 0 CH═CH H 243 H 0 CH═CH—CH═CH H 244 H 0 C≡C H 245 H 0 (CH═CH)2 H 246 H 0 CH═CH H 247 H 0 CH═CH H 248 H 0 CH═CH H 249 H 0 CH═CH H 250 H 0 CH═CH H 251 H 0 CH═CH—CH═CH H 252 H 0 CH═CH H 253 H 0 CH═CH H 254 H 0 CH═CH H 255 H 0 CH═CH—CH═CH H 256 H 0 CH═CH H 257 H 0 CH═CH—CH═CH H 258 H 0 CH═CH H 259 H 0 CH═CH H 260 H 0 CH═CH H 261 H 0 CH═CH—CH═CH H 262 H 0 C≡C H 263 H 0 CH═CH H 264 H 0 CH═CH H 265 H 0 CH═CH H 266 H 0 CH═CH H 267 H 0 CH═CH H 268 H 0 CH═CH—CH═CH H - Further subject-matter of the invention are analogous methods for the production of the compounds of formula (I) according to the invention.
- Method (A):
- Compounds of formula (I) are
-
-
- in which R1, R2, R3, A and k have the meaning described above or their reactive derivatives are reacted with compounds of formula (III)
- wherein D, E, G and R4 also have the above described meanings.
- in which R1, R2, R3, A and k have the meaning described above or their reactive derivatives are reacted with compounds of formula (III)
- Reactive derivatives of compound (II) can be, for example, activated esters, anhydrides, acid halides (especially acid chlorides) or simple low alkyl esters. Suitable activated esters are, for example, p-nitrophenyl ester, 2,4,6-trichlorophenyl ester, pentachlorophenyl ester, cyanomethyl ester, esters of N-hydroxysuccinimide, of N-hydroxyphthalimides, of 1-hydroxybenzotriazol, of N-hydroxypiperidine, of 2-hydroxypyridine or of 2-mercaptopyridine, etc. Anhydrides can be symmetric anhydrides or mixed, as they are obtained, for example, with pivaloyl chloride or with chloroformates. Aromatic (for example chloroformic phenyl ester), araliphatic (for example chloroformic benzyl ester) or aliphatic chloroformates (for example chloroformic methyl ester, -ethyl ester or -isobutyl ester) can be used for this.
- Reaction of compounds (II) with compounds (III) can also be carried out in the presence of condensation agents such as dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, N,N′-carbonyldiimidazol, 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline, etc. If carbodiimides are used as the condensation agent, reagents such as N-hydroxysuccinimide, N-hydroxyphthalimide, 1-hydroxybenzotriazol, N-hydroxypiperidine, etc. can be advantageously added.
- Compounds of formula (III) can be used for reaction as free bases as well as in the form of their acid addition salts. For this, the salts of inorganic acids are to be preferred, i.e. hydrochlorides, hydrobromides or sulfates.
- Reaction of compounds (II) or their reactive derivatives with compounds (III) are normally carried out in a suitable, preferably inert solvent. As examples, aromatic hydrocarbons such as benzene, toluene, xylene, halogenated hydrocarbons (for example dichloromethane, chloroform, 1,2-dichloroethane, trichloroethylene), ether (for example diethyl ether, tetrahydrofuran, dioxane, glycol dimethyl ether), ethyl acetate, acetonitrile or polar aprotic solvents such as, for example, dimethylsulfoxide, dimethylformamide or N-methylpyrrolidone are to be named. Pure solvents, as well as mixtures of two or more, can be used.
- The reaction is optionally carried out in the presence of an auxiliary base. Suitable examples for this are alkali metal carbonates (sodium carbonate, potassium carbonate), alkali metal hydrogen carbonates (sodium hydrogen carbonate, potassium hydrogen carbonate), or organic bases such as, for example, triethylamine, ethyl diisopropylamine, tributylamine, N-methylmorpholine or pyridine. A suitable excess of compound (III) can also be used as a base. If compounds (III) are used in form of their acid addition salts, then it is appropriate to consider the amount of auxiliary base used as equivalent.
- The reaction temperatures can—depending on reactivity of the educts—vary in a wide range. Generally, the reaction is carried out at temperatures between −40° C. and 180° C., preferably between −10° C. and 130° C., especially at the boiling point of the solvent used.
- The starting compounds (II) and (III) are known and/or can be produced according to known methods in an analogous manner. Moreover, the production of representative examples is further described below.
- Compounds of formula (I) can be
- (b) produced by reaction of compounds of formula (I), wherein G is hydrogen, and which themselves also have the activities found according to the invention, with a compound of formula (IV),
L-G (IV) - in which G has the meaning given above, with the exception of hydrogen, and L represents a suitable nucleofuge or reactive group. The type of nucleofuge or reactive group L and the conditions of the reaction are dependent of the nature of group G.
- Compounds of formula (I), in which G, with the exception of hydrogen, has the meaning of (G1) according to the above definition can, aside from method (a), also be
- (c) produced by reacting compounds of formula (I), in which G is hydrogen, with a suitable alkylation agent and/or arylation agent of formula (IV), wherein G is an alkyl-, alkenyl-, alkinyl-, cycloalkyl-, aryl-, aralkyl-, heteroaryl- or heteroaralkyl residue and the leaving group L can represent a reactive derivative of an alkohol, for example, a halogen atom such as chlorine, bromine or iodine or a sulfonic acid ester, i.e. for example a methanesulfonyloxy, trifluoromethanesulfonyloxy-, ethanesulfonyloxy-, benzenesulfonyloxy-, p-toluenesulfonyloxy, p-bromobenzenesulfonyloxy- or m-nitrobenzenesulfonyloxy residue, etc, or a reactive group L can also be an epoxide group, wherein the reaction occurs under addition.
- The reaction of compounds (I), in which G is a hydrogen, and (IV) is usually conducted in a suitably inert solvent. As solvents of this type, aromatic hydrocarbons (benzene, toluene, xylene), ethers (for example tetrahydrofuran, dioxane, glycol dimethyl ether), ethyl acetate, acetonitrile, ketones (acetone, ethyl methyl ketone), polar protic solvents such as alcohols (ethanol, isopropanol, butanol, glycol monomethyl ether) or polar aprotic solvents such as, for example, dimethylsulfoxide, dimethylformamide or N-methylpyrrolidone can be considered. Pure solvents as well as mixtures of two or more can also be used. Preferably, the reactions are carried out in the presence of bases, whereby said bases can be used as in method (a) above. If chlorides or bromides are used as compound (IV), the reaction can be accelerated by the addition of alkali metal iodides (sodium iodide, potassium iodide). The reaction temperatures can vary between 0° C. and 180° C. depending on the reactivity of the educts, but preferably lie between 20° C. and 130° C.
- Compounds of formula (I), in which G represents an acyl residue, a carbamoyl residue, a sulfonyl residue or a phosphinoyl residue according to the above definition, can also be produced, aside from the above method (a),
- (d) by reacting compounds of formula (I), wherein G is hydrogen, with a carboxylic acid, carbamic acid, sulfonic acid and/or phosphinic acid of formula (V),
HO-G (V) - wherein G is an acyl residue, carbamoyl residue, sulfonyl residue or phosphinoyl residue according to definition, or their derivatives capable of reaction. Preferred derivatives of carboxylic acids and/or sulfonic acids (V) which are capable of reaction are symmetric or unsymmetric carboxylic acid anhydrides and/or sulfonic acid anhydrides or acyl- and/or sulfonyl halides, especially acyl- and/or sulfonyl chlorides. Preferably, derivatives of carbonates and/or phosphinic acids which are capable of reaction are the carbamoyl halides and/or phosphinyl halides, especially carbamyl- and/or phosphinyl chlorides. The reaction of the acids (V) and/or their reactive derivatives with compounds (I), in which G is hydrogen, preferably occurs in the presence of auxiliary bases in solvents and under conditions as they are described in method (a).
-
- can also be produced, aside from the methods (a) and (d)
- (e) by reacting compounds of formula (I), in which G is hydrogen with a carbonyl group transmitter to an intermediate product and subsequently reacting this directly with a primary or secondary amine with the formula (VI)
H—NR12R14 (VI) - wherein R12 and R14 and/or the grouping —NR12R14 have the meanings according to the above definitions without having to purify or isolate the intermediate product.
- Bis-trichloromethyl carbonate (triphosgene) and carbonyldiimidazol have been proven as particularly reactive carbonyl group transmitters. The reaction of compounds of formula (I), wherein G is hydrogen, with triphosgene and/or carbonyldiimidazol are typically conducted in an absolute, inert solvent in the presence of a tertiary organic amine as an auxiliary base in such a manner that the solution of compounds (I) and the auxiliary base are slowly poured into a solution of an equivalent amount of carbonyl group transmitter. Thereby, the reaction requires molar ratios of 1:1 for the reaction of compound (I) and carbonyldiimidazol, and, in contrast, a ratio of 1:0.35 for the use of triphosgene. After complete reaction of the components to the intermediate product, compound (VI) is added in stochiometric amounts or in excess as a solution or a solid and the reaction is typically completed at elevated temperature. Suitable inert solvents are, for example hydrocarbons such as hexane, heptane, benzene, toluene, xylene, chlorinated hydrocarbons (for example dichloromethane, chloroform, 1,2-dichloroethane, trichloroethylene), ethers (for example diethyl ether, tetrahydrofuran, dioxane), esters such as ethyl acetate, butyl acetate, acetonitrile or polar aprodic solvents such as formamide or dimethylformamide. Pure solvents as well as mixtures can be used diversely. Sometimes it is of advantage to carry out the first partial reaction at low temperature in a low-viscosity, highly-volatile solvent and to remove the solvent after formation of the intermediate and replace it by a higher boiling solvent.
- Amines such as for example triethylamine, ethyl diisopropylamine, tributylamine, N-methylmorpholine or pyridine are suitable as auxiliary bases. If compounds (I) or (VI) are used as salts, the amount of the auxiliary base is increased accordingly. The reaction temperatures can lie in between −40° C. and 50° C. for the first partial reaction, preferably at 0° C. to 30° C., and between 0° C. and 150° C. for the second partial reaction, preferably at 20° C. to 120° C.
-
- can also be produced, side from methods (a), (d) and (e)
- (f) by reacting the compounds of formula (I) in which G is hydrogen, with an isocyanate of formula (VII) in which R12 has the meaning according to the above definition
O═C═N—R12 (VII). - Reaction of the compounds of formula (I), in which G is hydrogen, with the isocyanates of formula (VII) are conducted thereby in an absolute, inert solvent which can be a hydrocarbon such as pentane, hexane, heptane, benzene, toluene, or xylene, chlorinated hydrocarbons (such as dichloromethane, chloroform, 1,2-dichloroethane, trichloroethylene), ethers (for example, diethyl ether, tetrahydrofuran, dioxane), esters such as ethyl acetate, butyl acetate, or polar aprotic solvents such as formamide or dimethylformamide. mixtures of various solvents can also be used. Thereby, the reaction temperatures can vary in the region from −20° C. to 150° C., but preferably lie at 20° C. to 100° C.
- As already mentioned, the compounds of formula (I), wherein G is hydrogen, are themselves compounds with tumor growth inhibiting activity and/or cytostatic and immunosuppressive effectiveness. However, independent of their therapeutic applicability, they also represent useful intermediate compounds for the production of a multitude of other compounds according to the invention corresponding to (c) to (f).
- They themselves can, in principle, be produced according to method A by reacting a carboxylic acid of formula (II) with amines of formula (III) in which G is hydrogen as described above. However, since the compounds of formula (III) with hydrogen as G represent α,ω-diamines, the formation of product mixtures is always to be expected in their reaction with carboxylic acids (II) or their reactive derivatives making a subsequent separation necessary.
- In contrast, compounds of formula (I), in which G is hydrogen, are essentially more advantageously produced from other compounds of formula (I), in which G is a selectively cleavable group under mild conditions, i.e. corresponds to a nitrogen protective group.
- Among the compounds according to formula (I) with tumor growth inhibiting and/or cytostatic or immunomodulatory and/or immunosuppressive properties, are compounds in which G represents a 4-methoxybenzyl group, a triphenylmethyl group, a methoxy- and/or ethoxycarbonyl group, a tert-butoxycarbonyl group, an allyloxycarbonyl group or a trifluoroacetyl group. Thus, compounds of formula (I) with a 4-methoxybenzyl group as G are transformed into compounds of formula (I) with hydrogen as G by selective oxidation with ammonium-cer(IV)-nitrate for example. The cleavage of simple alkoxycarbonyl groups such as the methoxy- or ethoxycarbonyl group as well as the trifluoroacetyl group as G in compounds of formula (I) succeed by alkali hydrolysis under mild conditions without cleaving the A and D linked amide function. This is suitably valid for the cleavage of the triphenylmethyl group and the tert-butoxycarbonyl group as G in compounds of formula (I), which occurs in acidic medium under mild conditions. Finally, compounds of formula (I) with an allyloxycarbonyl group as G can be converted into such with hydrogen as G in neutral medium with palladium catalyst. All these methods are fully familiar to the person skilled in the art, and are furthermore also documented in monographs (see for example Greene, Wuts, Protective Groups in Organic Synthesis, New York, 1991).
- Compounds of formula (I), wherein R4 is an alkyl, alkenyl, alkinyl or cycloalkyl residue according to the above definition can also be produced, aside from the methods (a) and (b),
- (g) by reacting compounds of formula (I), wherein R4 is hydrogen, with a suitable alkylation agent of formula (VIII)
L-R4 (VIII) - wherein R4 is an alkyl, alkenyl, alkinyl or cycloalkyl residue according to the above definition and L is a suitable nucleofuge, i.e. for example a halogen atom such as chlorine, bromine or iodine or a sulfonic acid ester of an alcohol. Preferred sulfonic acid esters (VIII) contain a methylsulfonyloxy residue, trifluoromethanesulfonyloxy-, p-toluenesulfonyloxy-, p-bromobenzensulfonyloxy- or m-nitrobenzenesulfonyloxy residue as L.
- As an amide alkylation in the presence of tertiary amino groups, this reaction requires the use of strong auxiliary bases such as potassium-tert-butylate, sodium hydride, potassium hydride or butyl lithium in aprotic, inert solvents. Such solvents can be for example aliphatic or aromatic hydrocarbons (pentane, hexane, heptane, benzene, toluene), ethers (for example, tetrahydrofuran, dioxane) or polar solvents such as dimethylsulfoxide, dimethylformamide or N-methylpyrrolidone. Depending on the reactivity of the educts, the reaction temperatures can lie between −40° C. and 140° C. preferably between −20° C. and 80° C.
- The compounds of formula (I) produced according to the methods (a) to (g) can be isolated and purified in a known manner, for example by subjecting the residue after distillation of the solvent to partition, extraction, re-precipitation or re-crystallization or another purification method. For this, column chromatography on a suitable support or preparative, middle or high pressure liquid chromatography are preferred for this.
- The compounds (I) are first normally obtained in form of their free bases or their hydrates or solvates, depending on the type of isolation and purification. Their addition salts with pharmaceutically suitable acids are obtained in a typical manner by converting the base with the desired acid in a suitable solvent. Depending on the number of basic centers of compound (I), one or more equivalent acids per mole of base can be bound.
- Suitable solvents are, for example, chlorinated hydrocarbons such as dichloromethane or chloroform; ethers such as diethyl ether, dioxane or tetrahydrofuran; acetonitrile; ketones such as acetone or ethyl methyl ketone; esters such as methyl acetate or ethyl acetate or low molecular alcohols such as methanol, ethanol or isopropanol; and water. Pure solvents as well as mixtures of two or three solvents can also be used. The salts can be isolated by crystallization, precipitation or the evaporation of the solvent. Thereby, they optionally accumulate as hydrates or solvates.
- The bases can be recovered from the salts by alkalization, for example with aqueous ammonia solution, alkali carbonate or diluted sodium hydroxide solution.
- The following listed compounds and/or their pharmaceutically acceptable salts, if not already concretely labelled as such, are particularly preferred.
- N-[4-(1-methylsulfonylpiperidin-4-yl)-butyl]-3-(pyridin-3-yl)-acrylamide,
- N-{4-[1-(2-naphthylsulfonyl)-piperidin-4-yl]-butyl}-3-(pyridin-3-yl)-acrylamide,
- N-{4-[1-(2-naphthylsulfonyl)-piperidin-4-yl]-butyl}-5-(pyridin-3-yl)-2,4-pentadienoic acid amide,
- N-{4-[1-(1-naphthylaminocarbonyl)-piperidin-4-yl]-butyl}-3-pyridin-3-yl)-acrylamide,
- N-[4-(1-diphenylaminocarbonyl-piperidin-4-yl)-butyl]-3-(pyridin-3-yl)-acrylamide,
- N-[4-(1-diphenylaminocarbonyl-piperidin-4-yl)-butyl]-5-(pyridin-3-yl)-2,4-pentadienoic acid amide,
- N-{4-[1-(10,11-dihydrodibenzo[b,f]azepin-5-yl-carbonyl)-piperidin-4-yl-]-butyl}-3-(pyridin-3-yl)-acrylamide,
- N-[4-(1-diphenylphosphinoyl-piperidin-4-yl)-butyl]-3-(pyridin-3-yl)-acrylamide,
- N-[4-(1-acetylpiperidin-4-yl)-butyl]-3-(pyridin-3-yl)-acrylamide,
- N-[4-(1-diphenylacetyl-piperidin-4-yl)-butyl]-3-(pyridin-3-yl)-acrylamide,
- N-{4-[1-(3,3-diphenylpropionyl)-piperidin-4-yl]-butyl}-3-(pyridin-3-yl)-acrylamide,
- N-[4-(1-benzoylpiperidin-4-yl)-butyl]-3-(pyridin-3-yl)-acrylamide,
- N-[4-(1-benzoylpiperidin-4-yl)-butyl]-5-(pyridin-3-yl)-2,4-pentadienoic acid amide,
- N-{4-[1-(9-oxo-9H-fluoro-4-yl-carbonyl)-piperidin-4-yl]-3-butyl}-3-(pyridin-3-yl)-acrylamide,
- N-{4-[1-(phenylpyridin-3-yl-methyl)-piperidin-4-yl]-butyl}-3-(pyridin-3-yl)-acylamide,
- N-{4-[1-(phenylpyridin-4-yl-methyl)-piperidin-4-yl]-butyl}-3-(pyridin-3-yl)-acrylamide,
- N-{4-[1-(6,11-dihydrodibenzo[b,e]oxepin-11-yl-piperidin-yl]-butyl}-3-(pyridin-3-yl)-acrylamide,
- N-{4-[1-(6,11-dihydrodibenzo[b,e]thiepin-11-yl)-piperidin-4-yl]-butyl}-3-(pyridin-3-yl)-acrylamide,
- N-[7-(1-diphenylmethylpiperidin-4-yl)-heptyl]-3-(pyridin-3-yl)-acrylamide,
- N-[8-(1-diphenylmethylpiperidin-4-yl)-octyl]-3-(pyridin-3-yl)-acrylamide,
- N-[3-(1-diphenylmethylpiperidin-4-yloxy-propyl-3]-3-(pyridin-3-yl)-acrylamide,
- N-[3-(1-benzylpiperidin-4-yloxy)-propyl]-3-(pyridin-3-yl)-acrylamide,
- N-[2-(1-diphenylmethypiperidin-4-yl)-ethyl-5-]-(pyridin-3-yl)-2,4-pentadienoic acid amide,
- N-[4-(1-diphenylmethylpiperidin-4-yl)-butyl]-5-(pyridin-3-yl)-2,4-pentadienoic acid amide,
- N-[5-(1-diphenylmethylpiperidin-4-yl)-pentyl]-5-(pyridin-3-yl)-2,4-pentadienoic acid amide or
- N-[6-(1-diphenylmethylpiperidin-4-yl)-hexyl]-5-(pyridin-3-yl)-2,4-pentadienoic acid amide.
- In the following production examples for the end products, the abbreviations stand for the following terms:
- MP=melting point,
- RT=room temperature,
- THF=tetrahydrofuran,
- DMF=dimethylformamide,
- CDI=carbonyldiimidazol,
- abs.=absolute,
- EDC=N-(3-dimethylaminopropyl)-N′-ethyl-carbodiimide hydrochloride,
- HOBT=1-hydroxybenzotriazol,
- TEA=triethylamine.
- 1H-NMR-Spectrum=proton resonance spectrum, taken at 100 MHz. The chemical shifts are given in ppm against TMS as a standard (δ=0.0), whereby
- s=singlet,
- d=doublet,
- t=triplet,
- dt=doublet−triplet,
- m=multiplet,
- ar=aromatic,
- py=pyridine.
- 6.5 g (18.0 mmol) N-[4-piperidin-4-yl)-butyl]-3-(pyridin-3-yl)-acrylamide dihydrochloride (K22.142) and 5.77 ml (41.4 mmol) TEA are placed in 70 ml abs. dichlormethane and cooled to ca 0° C. under moisture exclusion. 4.58 g (19.8 mmol) N,N-diphenylcarbarnic acid chloride are dissolved in 20 ml abs. dichlormethane and added dropwise. The mixture is stirred at RT overnight without further cooling. 4 ml (28.7 mmol) TEA are added and the red colored suspension is stirred a further 2 hours at RT. Subsequently, the batch is washed with 80 ml water. The organic phase is dried over sodium sulfate and the solvent is removed under vacuum. The residue is chromatographically purified over silica gel with CHCl3/CH3OH (98/2) and crystallized twice, each from 60 ml acetic acid ethyl ester, after drawing off the solvent. Beige colored crystals with a MP of 132-134° C.; yield: 5.3 g (60%).
- C30H34N4O2 (482.6)
IR-spectrum (KBr): ν(NH) 3300cm−1 ν(C═O) 1660cm−1 1H-NMR-spectrum (CDCl3): 0.60-1.75(11H, m, piperidine, piperidine-(CH2)3) 2.40-2.85(2H, m, piperidine) 3.33(2H, dt, CONHCH 2, J=6.5Hz. J=12.7Hz) 3.85-4.20(2H, m, piperidine) 5.95-6.20(1H, m, NH) 6.42(1H, d, CH═CHCO, J=15.7Hz) 6.90-7.45(11H, m, ar, py) 7.59(1H, d, CH═CHCO, J=15.7Hz) 7.65-7.90(1H, m, py) 8.45-8.60(1H, m, py) 8.65-8.85(1H, m, py) - Production occurs analogously to example 1. However, no TEA is subsequently added.
- Batch size: 5.0 g (13.9 mmol) N-[4-(piperidin-4-yl)-butyl]-3-(pyridin-3-yl)-acrylamide dihydrochloride (substance 14 as a dihydrochloride), 5.8 ml (41.6 mmol) TEA and 3.9 g (15.2 mmol) diphenylacetic acid chloride,
- In the purification, this is washed twice, each with 50 ml water. The chromatographic purification is carried out with CHCl3/CH3OH (97/3 to 95/5). The residue is first crystallized twice, each from 15 ml acetic acid ethyl ester and then from 18 ml ethanol/diethyl ether (5/1). Colorless crystals remain with a MP of 161° C.; yield: 3.6 g (53%).
- C31H35N3O2 (481.6)
IR-spectrum (KBr): ν(NH) 3280cm−1 ν(C═O) 1665, 1530cm−1 ν(C═C) 1615cm−1 1H-NMR-spectrum (CDCl3): 0.50-1.85(11H, m, piperidine, piperidine-(CH2)3) 2.40-3.10(2H, m, piperidine) 3.32(2H, dt, CONHCH 2, J=6.5Hz. J=12.6Hz) 3.80-4.05(1H, m, piperidine) 4.55-4.80(1H, m, piperidine) 5.23(1H, Ar2CH) 6.10-6.35(1H, m, NH) 6.44(1H, d, CH═CHCO, J=15.7Hz) 7.10-7.45(11H, m, ar, py) 7.59(1H, d, CH═CHCO, J=15.7Hz) 7.60-7.85(1H, m, py) 8.50-8.65(1H, m, py) 8.65-8.80(1H, m, py) - Production occurs analogously to example 2.
- Batch size: 6.0 g (16.6 mmol) N-{4-[1-(piperidin-4-yl]-butyl}-3-(pyridin-3-yl)-acrylamide dihydrochloride (substance 14 as dihydrochloride), 5.6 ml (40.0 mmol) TEA and 2.5 g (11.0 mmol) naphthaline-2-sulfonic acid chloride in 70 ml abs. dichlormethane.
- In the work up, this is washed twice, each with 70 ml water. The chromatographic purification is carried out with CHCl3/CH3OH (95/5 to 94/6). The residue is crystallized from 30 ml acetic acid ethyl ester. Repeated chromatographic purification with CHCl31CH3OH (95/5). Yield: 2.7 g (57%); amorphic solid with a MP of 85-87° C.
- C27H31N3O3S (477.5)
IR-spectrum(KBr): ν(NH) 3320cm−1 ν(C═O) 1690, 1560cm−1 ν(C═C) 1640cm−1 1H-NMR-spectrum (CDCl3): 0.90-1.95(11H, m, piperidine, piperidine-(CH2)3) 2.10-2.50(2H, m, piperidine) 3.34(2H, dt, CONHCH 2, J=6.5Hz, J=12.5Hz) 3.65-4.00(2H, m, piperidine) 5.85-6.15(1H, m, NH) 6.46(1H, d, CH═CHCO, J=15.7Hz) 7.15-8.10(9H, m, ar, py. CH═CHCO) 8.33(1H, s, Ar) 8.50-8.65(1H, m, py) 8.65-8.80(1H, m, py) - 2.35 g (13.9 mmol) 1-naphthyl isocyanate are dissolved in 10 ml abs. THF and a solution of 4.0 g (13.9 mmol) N-{4-[1-(piperidin-4-yl]-butyl}-3-(pyridin-3-yl)-acrylamide (substance 14) in 30 ml abs. THF is added dropwise at RT under moisture exclusion. After ca. one hour, a white precipitate forms and the suspension is stirred at RT overnight. The solid is drawn off, chromatographically purified over silica gel with CHCl3/CH3OH (95/5 to 93/7) and crystallized from isopropanol after removal of the solvent. Colorless crystals remain with a MP of 198-200° C.; yield: 2.2 g (34%).
- C28H32N4O2 (456.6)
IR-spectrum (KBr): ν(NH) 3240cm−1 ν(C═O) 1660, 1560cm−1 ν(C═C) 1615cm−1 1H-NMR-spectrum (CDCl3): 1.00-1.95(11H, m, piperidine, piperidine-(CH2)3) 2.75-3.15(2H, m, piperidine) 3.37(2H, dt, CONHCH 2, J=6.5Hz. J=12.7Hz) 3.95-4.25(2H, m, piperidine) 5.75-6.05(1H, m, NH) 6.42(1H, d, CH═CHCO, J=15.6Hz) 6.70(1H, s, NH) 7.20-8.00(10H, m, ar, py. CH═CHCO) 8.50-8.65(1H, m, py) 8.65-8.80(1H, m, py) - 7.02 g (21.5 mmol) N-{4-[1-(piperidin-4-yl]-butyl}-3-(pyridin-3-yl)-acrylamide dihydrochloride (substance 14 as a dihydrochloride) are suspended in 100 ml abs. dichlormethane and added to 7.08 g (70.0 mmol) TEA. The mixture is cooled to ca. 0° C. under moisture exclusion and a solution of 5.30 g (21.5 mmol) 11-chlor-6,11-dihydro-dibenzo[b,e]thiepine in 10 ml abs. dichlormethane is added dropwise. The mixture is stirred for 24 hours at RT without further cooling. Subsequently, the batch is washed with 50 ml 10% sodium hydroxide solution and 30 ml water. The organic phase is dried over sodium sulfate and the solvent is removed under vacuum. The red brown residue is chromatographically purified three times over silica gel with CHCl3/CH3OH (100/0, 97/3 and 96/4 to 94/6). Subsequently, a further purification occurs by means of MPLC with CHCl1CH3OH (98/2). Yield: 0.5 g (5%) of a brittle, vitreous solid with a MP of 89-91° C.
- C31H35N3OS (497.7)
IR-spectrum (KBr): ν(NH) 3280cm−1 ν(C═O) 1660, 1550cm−1 ν(C═C) 1620cm−1 1H-NMR-spectrum (CDCl3): 0.90-2.00(13H, m, piperidine, piperidine-(CH2)3) 2.55-2.95(2H, m, piperidine) 3.20-3.60(3H, m, CONHCH 2, SCH2) 4.03(1H, Ar2CH) 6.10-6.35(1H, m, NH) 5.95-6.30(1H, m, SCH2) 6.44(1H, d, CH═CHCO, J=15.7Hz) 6.85-7.40(9H, m, ar, py) 7.61(1H, d, CH═CHCO, J=15.7Hz) 7.65-7.85(1H, m, py) 8.50-8.65(1H, m, py) 8.65-8.80(1H, m, py) - 3.85 g (22.0 mmol) 5-(3-pyridyl)-2,4-pentadienoic acid are suspended in 90 ml abs. dichlormethane and after addition of three drops of pyridine, cooled to ca 0° C. in an ice bath under moisture exclusion. 3.8 g (30.0 mmol) oxalyl chloride are added dropwise and the mixture is stirred a RT overnight. Subsequently, the solvent and excess oxalyl chloride is distilled off on a rotary evaporator. In order to completely remove the oxalyl chloride, the residue is dried for two hours under high-vacuum. The acid chloride obtained in this manner is suspended in 50 ml abs. dichloromethane and cooled to ca. 0° C. in an ice bath under moisture exclusion 6.44 g (20.0 mmol) 4-(1-diphenylmethylpiperidin-4-yl)-butylamine are dissolved in 40 ml abs. dichlormethane and added dropwise to this suspension. After complete addition, the ice bath is removed and the reaction is stirred for an additional two hours at RT. The mixture is subsequently washed with 10% sodium hydroxide solution. The organic phase is washed twice, each with 40 ml water, dried over sodium sulfate and the solvent is removed under vacuum. The residue is chromatographically purified over silica gel with CHCl3/CH3OH (98/2 to 95/5) and crystallized twice from 250 ml and 200 ml acetonitrile after drawing off the solvent. Beige colored crystals with a MP of 164-166° C.; yield: 4.7 g (49%).
- C32H37N3O (479.6)
IR-spectrum (KBr): ν(NH) 3280cm−1 ν(C═O) 1650, 1550cm−1 ν(C═C) 1600cm−1 1H-NMR-spectrum (CDCl3): 1.00-2.00(13H, m, piperidine, piperidine-(CH2)3) 2.70-3.00(2H, m, piperidine) 3.34(2H, dt, CONHCH 2, J=6.6Hz. J=12.8Hz) 4.21(1H, s, Ar2CH) 5.50-5.75(1H, m, NH) 6.44(1H, d, CH═CH, J=14.7Hz) 6.75-6.95(2H, m, CH═CH) 7.05-7.50(12H, m, ar, py. CH═CH) 7.65-7.85(1H, m, py) 8.45-8.55(1H, m, py) 8.60-8.75(1H, m, py) - 5.1 g (36.2 mMol) benzoyl chloride are dissolved in 150 ml abs. dichlormethane and cooled to ca 0° C. under moisture exclusion 10.4 g (36.2 mmol) N-[4-piperidin-4-yl) butyl]-3-(pyridin-3-yl)-acrylamide (substance 14) are dissolved in 50 ml abs. dichlormethane and added dropwise under ice cooling. The mixture is stirred overnight at RT without further cooling. Subsequently, the suspension is added to 60 ml 2 M sodium hydroxide and extracted twice, each with 80 ml dichlormethane. The combined organic phases are washed twice, each with 60 ml water, dried over sodium sulfate and the solvent is removed under vacuum. The residue is chromatographically purified over silica gel with CHCl3/CH3OH (97/3 to 95/5) and recrystallized from 75 ml acetonitrile. Colorless crystals with a MP of 100-102° C. are recovered; yield: 9.8 g (69%).
- C24H29N3O2 (391.5)
IR-spectrum (KBr): ν(NH) 3280cm−1 ν(C═O) 1670, 1545cm−1 ν(C═C) 1630cm−1 1H-NMR-spectrum (CDCl3): 0.80-2.00(11H, m, piperidine, piperidine-(CH2)3) 2.55-4.00(5H, m, piperidine, CONHCH 2) 4.40-4.90(1H, piperidine) 6.00-6.25(1H, m, NH) 6.48(1H, d, CH═CHCO, J=15.7Hz) 7.15-7.95(8H, m, ar, py. CH═CHCO) 8.50-8.65(1H, m, py) 8.65-8.80(1H, m, py) - Production occurs analogously to example 6.
- Batch size: 4.3 g (28.7 mmol) 3-(3-pyridyl)-acrylic acid, 6.7 ml (78.4 mmol) oxalyl chloride and 6.6 g (26.1 mmol) (1-diphenylmethyl-azetidin-3-ylmethyl)-amine.
- In the work up, the reaction mixture is washed with 10% sodium hydroxide solution. The aqueous phase is extracted twice, each with 50 ml dichlormethane. The combined organic phases are dried over sodium sulfate and the solvent is removed under vacuum. The residue is chromatographically pre-purified over silica gel with CHCl3/CH3OH (98/2 to 95/5) and subsequently purified by two-fold flash-chromatography with CHCl3/CH3OH (99/1 to 95/5). After drawing off the solvent, an amorphous solid remains with a MP of 72-74° C.; yield: 0.75 g (7%).
- C3H25N3O (383.5)
IR-spectrum (KBr): ν(NH) 3320cm−1 ν(C═O) 1680, 1570cm−1 ν(C═C) 1640cm−1 1H-NMR-spectrum (CDCl3): 2.40-2.80(1H, m, azetidine) 2.80-3.10(2H, m, azetidine) 3.10-3.40(2H, m, azetidine) 3.60(2H, dd, CONHCH 2, J=5.7Hz) 4.36(1H, Ar2CH) 6.45-6.75(1H, m, NH) 6.50(1H, d, CH═CHCO, J=15.7Hz) 7.00-7.50(11H, m, ar, py) 7.62(1H, d, CH═CHCO, J=15.7Hz) 7.65-7.90(1H, m, py) 8.50-8.70(1H, m, py) 8.70-8.85(1H, m, py) - Production occurs analogously to example 6.
- Batch size: 2.3 g (15.6 mmol) 3-(3-pyridyl)-acrylic acid, 5.4 g (42.5 mmol) oxalyl chloride and 3.6 g (14.7 mmol) 2-aminomethyl-4-diphenylmethylmorpholine.
- In the work up, 40 ml 10% sodium hydroxide solution are added to the reaction solution. The aqueous phase is extracted with 15 ml dichlormethane. The combined organic phases are washed twice, each with 15 ml water, dried over sodium sulfite and the solvent is removed under vacuum. The residue is chromatographically purified three times over silica gel with CHCl3/CH3OH (95/5, 90/10 and 90/10). After drawing off the solvent, an amorphous solid remains with a MP of 71-74° C.; yield: 0.8 g (13%).
- C26H27N3O2 (413.5)
IR-spectrum (KBr): ν(NH) 3270cm−1 ν(C═O) 1655, 1540cm−1 ν(C═C) 1620cm−1 1H-NMR-spectrum (CDCl3): 1.70-2.30(2H, m, morpholine) 2.55-2.90(2H, m, morpholine) 3.00-3.35(1H, m, morpholine) 3.50-4.00(4H, m, CONHCH 2, morpholine) 4.20(1H, Ar2CH) 6.00-6.25(1H, m, NH) 6.47(1H, d, CH═CHCO, J=15.7Hz) 7.00-7.55(11H, m, ar, py) 7.60(1H, d, CH═CHCO, J=15.7Hz) 7.65-7.90(1H, m, py) 8.50-8.70(1H, m, py) 8.70-8.80(1H, m, py) - 5.0 g (20.0 mmol) 95% 9-fluorenon-4-carboxylic acid chloride are dissolved in 70 ml abs. dichlormethane and 6.5 g (18.2 mmol) N-[4-(piperidin-4-yl)-butyl]-3-(pyridin-3-yl)-acrylamide dihydrochloride (substance 14 as a dihydrochloride) are added. The mixture is cooled to ca. 0° C. under moisture exclusion and 4.0 g (40.0 mmol) TEA dissolved in 10 ml abs. dichlormethane are added dropwise. The batch is stirred at RT overnight without further cooling. In the work up, 150 ml 10% A sodium hydroxide solution are added to the reaction solution and this is extracted by shaking. The organic phase is washed with 100 ml water, dried over sodium sulfate and the solvent is removed under vacuum. The residue is pre-purified over silica gel with CHCl3/CH3OH (96/4 to 95/5) and subsequently purified by flash-Chromatography with CHCl3/CH3OH (95/5). After drawing off the solvent, the product remains as a yellow vitreous solid with a MP of 80-82° C.; yield: 2.3 g (25%).
- C31H31N3O3 (493.6)
IR-spectrum (KBr): ν(NH) 3320cm−1 ν(C═O) 1730, 1640cm−1 ν(C═C) 1620cm−1 1H-NMR-spectrum (CDCl3): 0.70-2.05(11H, m, piperidine, piperidine-(CH2)3) 2.60-3.80(5H, m, piperidine, CONHCH 2) 4.70-5.05(1H, piperidine) 5.85-6.20(1H, m, NH) 6.47(1H, d, CH═CHCO, J=15.7Hz) 7.15-7.90(10H, m, ar, py. CH═CHCO) 8.50-8.65(1H, m, py) 8.65-8.85(1H, m, py) - 2.4 g (16.2 mmol) 3-(3-pyridyl)-acrylic acid and 2.3 ml (16.2 mmol) TEA are suspended in 50 ml abs. toluene and a solution of 1.5 ml (15.5 mmol)-chloroformic acid ethyl ester in 20 ml abs. toluene are added dropwise under moisture exclusion and light cooling. This yellow suspension is stirred at RT for two hours and then a solution of 3.5 g (14.1 mmol) 3-(1-benzylpiperidin-4-yloxy)-propylamine in 20 ml abs. toluene is added dropwise. The mixture is stirred for two hours at RT and extracted by shaking three times in the heat each with 10 ml water, 2 M sodium hydroxide and water again. The organic phase is concentrated under vacuum and the orange colored oily residue is chromatographically purified twice over silica gel with CHCl3/CH3OH/NH4OH (90/9/1 and 95/5/0 to 90/10/0) and crystallized from 10 ml acetic acid ethyl ester. Colorless crystals remain with a MP of 100-102° C.; yield: 1.9 g (35%).
- C23H29N3O2 (379.5)
IR-spectrum (KBr): ν(NH) 3290cm−1 ν(C═O) 1650, 1530cm−1 ν(C═C) 1610cm−1 1H-NMR-spectrum (CDCl3): 1.50-2.45(8H, m, piperidine, C—CH2—C) 2.70-3.00(2H, m, piperidine) 3.25-3.80(7H, m, piperidine, CONHCH 2, Ar—CH2, O—CH2) 6.54(1H, d, CH═CHCO, J=15.7Hz) 6.70-6.95(1H, m, NH) 7.25-7.50(6H, m, ar, py) 7.69(1H, d, CH═CHCO, J=15.7Hz) 7.80-8.00(1H, m, py) 8.60-8.75(1H, m, py) 8.75-8.90(1H, m, py) - 1.79 g (12.0 mmol) 3-(pyridyl)-acrylic acid and 4.0 g (39.5 mmol) TEA are suspended in 80 ml abs. dichloromethane and cooled to ca. 0° C. under moisture exclusion. 2.2 g (14.3 mmol) 88% HOBT and 2.76 g (14.4 mmol) EDC are added and the mixture is stirred 30 min under ice cooling. 5.6 g (12.0 mmol) 1-diphenylmethylpiperidin-3-carboxylic acid-(6-amino-hexyl)-amide dihydrochloride are added and the mixture is stirred overnight at RT without cooling. Subsequently, the batch is washed twice with sodium hydroxide with 50 ml 2M sodium hydroxide solution and 70 ml water. The organic phase is dried over sodium sulfate and the solvent is removed under vacuum. The residue is chromatographically purified over silica gel with CHCl3/CH3OH (96/4 to 95/5) and crystallized from 70 ml acetonitrile. Colorless crystals remain with a MP of 129-131° C.; yield: 3.9 g (62%).
- C33H40N4O2 (524.7)
IR-spectrum (KBr): ν(NH) 3300cm−1 ν(C═O) 1640, 1540cm−1 ν(C═C) 1620cm−1 1H-NMR-spectrum (CDCl3): 1.20-2.95(17H, m, piperidine, C—(CH2)4—C) 3.15-3.55(4H, m, CONHCH 2) 4.24(1H, Ar2CH) 6.30-6.55(1H, m, NH) 6.57(1H, d, CH═CHCO, J=15.7Hz) 7.05-7.45(11H, m, ar, py) 7.62(1H, d, CH═CHCO, J=15.7Hz) 7.65-8.00(2H, m, py. NH) 8.50-8.60(1H, m, py) 8.65-8.80(1H, m, py) - 1.06 ml (5.55 mmol) diphenylphosphinic acid chloride are dissolved in 20 ml abs. THF and cooled to ca. 0° C. under moisture exclusion. 2.0 g (5.55 mmol) N-[4-(piperidin-4-yl)-butyl]-3-(pyridin-3-yl)-acrylamide dihydrochloride (substance 14 as a dihydrochloride) and 2.3 ml (16.6 mmol) TEA are suspended in 90 ml abs. THF and added dropwise under ice cooling. The mixture is stirred for four days at RT without further cooling. Subsequently the solvent is removed under vacuum and the residue is taken up in 70 ml 10% sodium hydroxide solution and twice, each with 100 ml CHCl3. The combined organic phases are washed with saturated NaCl solution, dried over sodium sulfate and the solvent is removed under vacuum. The residue is pre-purified over silica gel with CHCl3/CH3OH (90/10), subsequently further purified by flash-chromatography with CHCl3/CH3OH (90/10) and crystallized from 30 ml acetic acid ethyl ester. Colorless crystals remain with a MP of 154-155° C.; yield: 1.04 g (30%).
- C29H34N3O2P (487.6)
IR-spectrum (KBr): ν(NH) 3260cm−1 ν(C═O) 1650, 1550cm−1 ν(C═C) 1610cm−1 1H-NMR-spectrum (CDCl3): 0.90-1.80(11H, m, piperidine, piperidine-(CH2)3) 2.55-2.95(2H, m, piperidine) 3.10-3.55(4H, m, piperidine, CONHCH 2) 6.59(1H, d, CH═CHCO, J=15.7Hz) 6.55-6.80(1H, m, NH) 7.15-8.00(13H, m, ar, py. CH═CHCO) 8.50-8.60(1H, m, py) 8.60-8.80(1H, m, py) - Production occurs analogously to example 6.
- Batch size: 2.6 g (17.4 mmol 3-(3-pyridyl)-acrylic acid, 1.6 ml (19.0 mmol) oxalyl chloride and 3.9 g (15.8 mmol) 4-(1-benzyl-piperidin-3-yl)-butylamine in 100 ml abs. dichlormethane.
- The reaction time is prolonged to 6 hours at RT. In the work up, the batch is washed with 50 ml 1 M sodium hydroxide solution and the aqueous phase is extracted with 50 ml dichlormethane. The combined organic phases are concentrated under vacuum and the residue is chromatographically pre-purified twice over silica gel with CHCl3/CH3OH (93/7 and 95/5), subsequently purified further by flash-chromatography with CHCl3/CH3OH (95/5 and 97/3) and crystallized from 5 ml acetic acid ethyl ester. Colorless crystals remain with a MP of 80-82° C.; yield: 0.9 g (15%).
- C24H31N3O (377.5)
IR-spectrum (KBr): ν(NH) 3300cm−1 ν(C═O) 1650, 1530cm−1 ν(C═C) 1610cm−1 1H-NMR-spectrum (CDCl3): 1.00-2.10(13H, m, piperidine, piperidine-(CH2)3) 2.65-2.95(2H, m, piperidine) 3.37(2H, dt, CONHCH 2, J=6.5Hz J=12.7Hz) 3.50(2H, s, Ar—CH2) 5.65-5.95(1H, m, NH) 6.46(1H, d, CH═CHCO, J=15.6Hz) 7.10-7.40(6H, m, ar, py) 7.62(1H, d, CH═CHCO, J=15.6Hz) 7.65-7.90(1H, m, py) 8.50-8.65(1H, m, py) 8.70-8.80(1H, m, py) - Production occurs analogously to example 6. TEA is also added dropwise with the addition of the amine.
- Batch size: 16.4 g (110 mmol) 3-(3-pyridyl)-acrylic acid, 18.9 g (150 mmol) oxalyl chloride, 25.6 g (100 mmol) 4-(1-tert-butoxycarbonyl-piperidin-4-yl)-butylamine and 10.1 g (100 mmol) TEA in 300 ml abs. dichlormethane.
- In the work up, 100 ml 10% sodium hydroxide solution are added to the reaction solution. The aqueous phase is extracted with 30 ml dichlormethane. The combined organic phases are washed twice, each with 25 ml water, and the solvent is removed under vacuum. The residue is dissolved in CHCl3/CH3OH (90/10) and filtered through a thin silica gel layer. After drawing off the solvent, the crude product remains as a red oil (44.0 g). For purification, this is chromatographed with CHCl3/CH3OH (95/5) on silica gel. Yield: 26.5 g (68%) as a yellow viscous oil.
- C22H33N3O3 (387.50)
IR-spectrum (KBr): ν(NH) 3250cm−1 ν(C═O) 1670, 1540cm−1 ν(C═C) 1600cm−1 1H-NMR-spectrum (CDCl3): 0.80-1.90(20H, m, piperidine, piperidin-(CH2)3, tert, butyl) 2.30-2.90(2H, m, piperidine) 3.10-3.60(2H, m, piperidine) 3.80-4.30(2H, m, CONHCH 2) 6.15-6.55(1H, m, NH) 6.43(1H, d, CH═CHCO, J=15.6Hz) 7.05-7.85(2H, m, py) 7.51(1H, d, CH═CHCO, J=15.6Hz) 8.35-8.55(1H, m, py) 8.55-8.70(1H, m, py) - 44.0 g (<113.5 mmol) crude N-{4-[N-(tert-butoxycarbonyl)-piperidin-4-yl]-butyl}-3-(pyridin-3-yl)-acrylamide (substance 242) are dissolved in 400 ml ethanol and added to 26.0 ml conc. hydrochloric acid. The mixture is heated to boiling for three hours and, after cooling the solvent is removed under vacuum. The yellow residue is crystallized from 500 ml isopropanol. Beige colored crystals remain with a MP of 178-188° C.; yield: 32.6 g (90%).
- C17H25N3O.2HCl (360.3)
IR-spectrum (KBr): ν(NH) 3260cm−1 ν(C═O) 1670, 1545cm−1 ν(C═C) 1630cm−1 1H-NMR-spectrum (D2O): 0.95-1.95(11H, m, piperidine, piperidine-(CH2)3) 2.60-3.00(2H, m, piperidine) 3.00-3.40(4H, m, piperidine, CONHCH 2) 6.73(1H, d, CH═CHCO, J=15.9Hz) 7.41(1H, d, CH═CHCO, J=15.9Hz) 7.80-8.00(1H, m, py) 8.50-8.65(2H, m, py) 8.65-8.90(1H, m, py) - The invention is more closely illustrated by means of the further synthesis examples listed in the following Table 2, without restricting the invention.
TABLE 2 Prepared compounds of formula (I) MP [° C.] Nr R1 A D—E—G (solvent)2 1 H CH═CH 72-74 (amorph; CHCl3/MeOH) 4 H CH═CH 164-165 (EE) 14 H CH═CH 140-142 (amorph; CH2Cl2) 14 H CH═CH 178-1882(iPrOH) 15 H CH═CH—CH═CH 197-2022(iPrOH) 39 H CH═CH 100-102 (EE) 40 H CH═CH 80-82 (EE) 54 H CH═CH 135-136 (EE) 59 H CH═CH 221-223 (MeOH) 62 H CH═CH 139-140 (EE) 63 ca. 205 (Zers.) (CHCl3) 65 H 142-144 (MeCN) 70 H CH═CH—CH═CH 164-166 (MeCN) 97 H CH═CH 178-180 (EE) 103 H CH═CH 129-131 (MeCN) 107 H CH═CH 190-192 (MeCN) 134 H CH═CH 139-141 (EE) 136 H CH═CH 89-91 (amorph; CHCl3/MeOH) 140 H CH═CH Hars3 150 H CH═CH 161 (EtOH/Et2O) 151 H CH═CH—CH═CH 77-79 (EE/BuCl) 153 H CH═CH 105-106 (MeCN/MTBE) 159 H CH═CH 100-102 (MeCN) 162 H CH═CH—CH═CH 133-135 (EE/BuCl) 178 H CH═CH 80-82 (amorph; CHCl3/MeOH) 195 H CH═CH 198-200 (iPrOH) 199 H CH═CH 132-134 (EE) 200 H CH═CH—CH═CH 146-148 (iPrOH) 219 H CH═CH 85-87 (amorph; CHCl3/MeOH) 232 H CH═CH 154-155 (EE) 242 H CH═CH Ol3 243 H CH═CH—CH═CH 135-136 (EE) 250 H CH═CH 71-74 (amorph; CHCl3/MeOH)
Table annotation
1MeOH = methanol
EE = ethyl acetate
iPrOH = isopropanol
MeCN = acetonitrile
EtOH = ethanol
Et2O = diethyl ether
BuCl = 1-chlorobutane
MTBE = methyl tert-butyl ether
2as a dihydrochloride
3purified by column chromatography
- Several examples for the production of the starting compounds are described in the following for the better illustration of the production of the end products.
- 100 g (458 mmol) 4-piperidin-4-yl-butan-1-ol hydrochloride are dissolved in 120 ml water, added to 216 ml (1550 mmol) TEA and cooled to ca. 5-10° C. 122 g (559 mmol) di-tert-butyl dicarbonate are dissolved in 400 ml THF and added dropwise within four hours under further cooling. The mixture is left to stand without further cooling at RT overnight. Subsequently, the THF is removed under vacuum to a large extent and the residue is extracted twice, each with 300 ml and 200 ml CHCl3 respectively, and the combined organic phases are washed twice, each with 20 ml water. The solvent is removed under vacuum. The residue is dried under high-vacuum and processed further without additional purification Yield: 136 g (102%).
- 136 g (528 mmol) 4-[1-tert-butoxycarbonylpiperidin-4-yl)-butan-1-ol (crude product), 135.3 g (516 mmol) Triphenylphosphine and 75.9 g (516 mmol) phthalimide are suspended in 1800 ml THF and 89.9 g (516 mmol) azodicarboxylic acid diethyl ester are added dropwise within three hours under protective atmosphere and light cooling (to ca. 15° C.). The mixture is left to stand at RT overnight without further cooling. Subsequently, the solvent is removed under vacuum and the oily residue is dissolved in 500 ml acetic acid ethyl ester and held at 0° C. overnight. The sedimented precipitate is filtered and discarded. The solution is concentrated under vacuum and the oily residue is chromatographically purified over silica gel with CHCl3 and crystallized from 200 ml isopropanol after drawing off the solvent. Colorless crystals remain with a MP of 100-102° C.; yield: 108.5 g (57%).
- 113.0 g (292 mmol) 2-[4-(1-tert-butoxycarbonylpiperidin-4-yl)-butyl]-isoindol-1,3-dione are dissolved in 600 ml ethanol added to 29.3 g (585 mmol) hydrazine hydrate and heated to boiling for three hours. After cooling the solution, the mixture is filtered and the filtrate is concentrated under vacuum. The residue is dispersed in the heat (ca. 50° C.) between 500 ml toluene and 500 ml 10% sodium hydroxide solution. The organic phase is washed once with 50 ml 10% sodium hydroxide solution and twice, each with 50 ml water. The solvent is removed under vacuum and the residue is dried at 70° C. under high-vacuum and processed further without additional purification. Yield of colorless oil: 64.0 g (85%).
- A solution of 10.0 g (40 mmol) 1-diphenylmethyl-azetidin-3-carbonitrile in 20 ml abs. THF is added dropwise to a suspension of 3.1 g (80 mmol) lithium aluminium hydride in 80 ml abs. THF at RT and stirred overnight. The batch is carefully added to 2 ml ethanol and filtered. The filtrate is concentrated under vacuum and dispersed between CHCl3 and water. The aqueous phase is extracted twice, each with 50 ml CHCl3, and the combined organic phases are dried over sodium sulfate and the solvent is removed under vacuum. The residue is chromatographically purified over silica gel with CHCl3/CH3OH/NH4OH (90/10/0 to 90/10/1). Yield: 5.6 g (55%) of slowly hardening resin.
- 10.0 g (40.9 mmol) 3-(1-benzylpiperidin-4-yloxy)-propionitrile are dissolved in 100 ml ethanol and added to a spatula tip of Raney-Nickel. The mixture is stirred at RT under hydrogen atmosphere until the uptake of the theoretical amount of hydrogen (ca. two days). The mixture is filtered from the catalyst and the solvent is removed under vacuum. The residue is distilled in a bulb tube apparatus. Yield of colorless oil: 7.5 g (73%).
- 15.7 g (100 mmol) piperidin-3-carboxylic acid ethyl ester and 30.4 g (220 mmol) potassium carbonate are placed in 100 ml DMF and 24.1 g diphenyl methyl bromide are added dropwise. The mixture is stirred overnight at RT and subsequently filtered. The filtrate is concentrated under vacuum and the residue is taken up with 150 ml acetic acid ethyl ester and extracted twice, each with 50 ml 10% hydrochloric acid. The organic phase is discarded and the combined aqueous phases are made basic with 10% sodium hydroxide solution and extracted twice, each with 50 ml acetic acid ethyl ester. The combined organic phases are cooled to ca. 0° C. and the precipitated solid is drawn off and dried. Yield: 20.5 g (63%) of the compound 1-diphenylmethyl-piperidin-3-carboxylic acid ethyl ester with a MP of 166-168° C. This compound is heated to boiling for 8 hours together with 24 ml 20% hydrochloric acid in 100 ml water. After cooling, the precipitate is filtered and crystallized from 70 ml methanol. Yield: 15.6 g (74%).
- 10.0 g (33.8 mmol) 1-diphenylmethylpiperidin-3-carboxylic acid hydrochloride are reacted analogously to example 6 with 8.6 g (68 mmol) oxalyl chloride to the acid chloride. This is suspended in abs. dichlormethane and added to 6.64 g (30.7 mmol) N-(tert-butoxycarbonyl)-hexanediamine and 3.1 g (30.7 mmol) TEA and stirred at RT overnight. The mixture is subsequently concentrated, taken up in CHCl3 and washed once with 50 ml 10% sodium hydroxide solution and twice with 30 ml water each. The organic phase is dried over sodium sulfate and the solvent is removed under vacuum. The residue is chromatographically purified over silica gel with CHCl3/CH3OH (100/0 to 98/2) and dissolved in 80 ml ethanol. After addition of 6 ml conc. hydrochloric acid, the mixture is heated to boiling for 5 hours. After cooling, the solvent is removed under vacuum and the residue is azeotropically dehydrated twice, each with 30 ml toluene, and subsequently dried under high-vacuum. The resin is further processed without additional purification Yield: 6.8 g (71%).
- 77.3 g (188.3 mmol) 3-cyanopropyl-triphenylphosphonium bromide are suspended in 300 ml toluene and added to 22.0 g (191.9 mmol) potassium tert-butylate. The mixture is cooled to ca. 0° C. under moisture exclusion and a solution of 34.6 g (182.8 mmol) 1-benzyl-3-piperidone in 50 ml toluene is added dropwise under cooling. The batch is left to stand overnight at ca. 0° C. and subsequently diluted with 200 ml toluene and washed twice, each with 100 ml water. The organic phase is extracted with 150 ml half concentrated hydrochloric acid. Subsequently, the aqueous phase is made basic with 200 ml 10% sodium hydroxide solution and extracted twice each with 250 ml toluene. The solvent is removed under vacuum and the residue is chromatographically purified over silica gel with CHCl3/CH3OH (97/3). After drawing off the solvent, a light brown oil remains which is processed further without additional purification. Yield: 47.4 g (90%).
- 8.0 g (33.3 mmol) 4-(1-benzylpiperidin-3-yliden)-butyronitrile are dissolved in 80 ml ethanol and added to a spatula tip of Raney-Nickel. The mixture is stirred at ca. 50° C. under hydrogen atmosphere until consumption of the theoretischen amount of hydrogen to be taken up (ca. 5 days). The mixture is filtrated from the catalyst and the solvent is removed under vacuum. The residue is chromatographically purified twice over silica gel with CHCl3/CH3OH/NH4OH (90/10/1). After drawing off the solvent, a colorless oil remains which is further processed without additional purification. Yield: 3.9 g (47%).
- The active ingredients according to the invention can be processed to the desired medicaments in the form of their acid addition salts, hydrates or solvates individually or in combination with each other, optionally under addition of other active ingredient, for the indications tumor treatment or immunosuppression. In the case of the combination of active ingredients according to the invention with other medicinal forms, these can also optionally be separately present next to each other in the medicine packaging, for example as tablets next to vials, depending on the requirements.
- Therefore, further subject-matter of the invention is a method for the treatment of the human or animal body in which a compound or compound mixture according to formula (I), wherein the substituents have the above described meaning, is administered for treatment of tumors and/or as a cytostatic agent, cancerostatic agent, immunosuppressing agent, optionally in combination with further cytostatic or immunosuppressive active ingredients or other active ingredients suitable in the named indications.
- Furthermore, the invention relates to a compound or compound mixture according to formula (I) for use in a therapeutic method in which the therapeutic use is carried out in connection with one or more medical indications with tumors or for immunosuppression, optimally in combination with further pharmaceuticals suitable in the named indications.
- The use of one or more compounds according to formula (I), including (E)-3-(3-pyridyl)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-2-propenamide hydrochloride, for the production of medicaments for the treatment of the human or animal body, especially in connection with one or more medical indications in the treatment of tumors or for immunosuppression, optimally in combination with further pharmaceuticals suitable in these indications or the use of compounds according to formula (I) in a corresponding diagnosis method represent an embodiment according to the invention.
- The respective suitable tumor indications are illustrated in the last section of the description in the discussion of the pharmacological test results.
- A method for the production of medicaments with an amount of one or more compounds according to formula (I) which are suitable for the processing of these active ingredients together with respective suitable pharmaceutically acceptable carriers and adjuvants for finished medicinal forms equally belongs to the scope of protection according to the invention.
- Depending on the medical indication being considered, the respective suitable medical form is selected for the suitable therapeutic application.
- The invention also relates to the use of the compounds according to formula (I), including (E)-3-(3-pyridyl)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-2-propenamide hydrochloride, for treatment in the above indications.
- The production of the respective suitable medicaments as well as a series of examples of medicinal forms are described in the following for better understanding of the invention.
- The production of medicaments with an amount of one or more compounds according to the invention and/or their use in the application according to the invention occurs in the customary manner by means of common pharmaceutical technology methods. For this, the active ingredients as such or in the form of their salts are processed together with suitable, pharmaceutically acceptable adjuvants and carriers to medicinal forms suitable for the various indications and types of application. Thereby, the medicaments can be produced in such a manner that the respective desired release rate is obtained, for example a quick flooding and/or a sustained or depot effect.
- Preparations for parenteral use, to which injections and infusions belong, are among the most important systemically employed medicaments for tumor treatment as well as for other indications.
- Preferably, injections are administered for the treatment of tumors. These are prepared either in the form of vials or also as so-called ready-to-use injection preparations, for example as ready-to-use syringes or single use syringes in addition to perforation bottles for multiple withdrawals. Administration of the injection preparations can occur in the form of subcutaneous (s.c.), intramuscular (i.m.), intravenous (i.v.) or intracutaneous (i.c.) application. The respective suitable injection forms can especially be produced as solutions, crystal suspensions, nanoparticular or colloid-disperse systems, such as for example, hydrosols.
- The injectable formulations can also be produced as concentrates which can be adjusted with aqueous isotonic dilution agents to the desired active ingredient dosage. Furthermore, they can also be produced as powders, such as for example lyophilisates, which are then preferably dissolved or dispersed immediately before application with suitable diluents. The infusions can also be formulated in the form of isotonic solutions, fat emulsions, liposome formulations, microemulsions and liquids based on mixed micells, for example, based on phospholipids. As with injection preparations, infusion formulations can also be prepared in the form of concentrates to dilute. The injectable formulations can also be applied in the form of continuous infusions as in stationary as well as in out-patient therapy, for example in the form of mini-pumps.
- Albumin, plasma expanders, surface active compounds, organic solvents, pH influencing compounds, complex forming compounds or polymeric compounds can be added to the parenteral medicinal forms, especially as substances for influencing the adsorption of the active ingredients to protein or polymers or also with the aim of decreasing the adsorption of the active ingredient to materials such as injection instruments or packaging materials, for example plastic or glass.
- The active ingredients can be bound to nanoparticles in the preparations for parenteral use, for example on finely dispersed particles based on poly(meth)acrylates, polyacetates polyglycolates, polyamino acids or polyether urethanes. The parenteral formulations can also be constructively modified as depot preparations, for example on the multiple unit principle, where the active ingredients are incorporated in a most finely distributed and/or dispersed, suspended form or as crystal suspensions, or on the single unit principle, where the active ingredient is enclosed in a medicinal form, for example, a tablet or a seed which is subsequently implanted. Often, these implantations or depot medicaments in single unit and multiple unit medicinal forms consist of so-called biodegradable polymers, such as for example, polyether urethanes of lactic and glycolic acid, polyether urethanes, polyamino acids, poly(meth)acrylates or polysaccharides.
- Sterilized water, pH value influencing substances, such as for example organic and inorganic acids or bases as well as their salts, buffer substances for setting the pH value, agents for isotonicity, such as for example sodium chloride, monosodium carbonate, glucose and fructose, tensides and/or surface active substances and emulsifiers, such as for example, partial fatty acid esters of polyoxyethylene sorbitan (Tween®) or for example fatty acid esters of polyoxethylene (Cremophor®), fatty oils such as for example peanut oil, soybean oil and castor oil, synthetic fatty acid esters, such as for example ethyl oleate, isopropyl myristate and neutral oil (Miglyol®) as well as polymer adjuvants such as for example gelatin, dextran, polyvinylpyrrolidone, organic solvent additives which increase solubility, such as for example propylene glycol, ethanol, N,N-dimethylacetamide, propylene glycol or complex forming compounds such as for example citrates and urea, preservatives, such as for example hydroxypropyl benzoate and hydroxymethyl benzoate, benzyl alcohol, anti-oxidants, such as for example sodium sulfite and stabilizers, such as for example EDTA, are suitable as adjuvants and carriers in the production of preparations for parenteral use.
- In suspensions, addition of thickening agents to prevent the settling of the active ingredients from tensides and peptizers, to sure the ability of the sediment to be shaken, or complex formers, such as EDTA, ensues. This can also be achieved with the various polymeric agent complexes, for example with polyethylene glycols, polystyrol, carboxymethylcellulose, Pluronics® or polyethylene glycol sorbitan fatty acid esters. The active ingredient can also be incorporated in liquid formulations in the form of inclusion compounds, for example with cyclodextrins. As further adjuvants, dispersion agents are also suitable. For production of lyophilisates, builders are also used, such as for example mannite, dextran, saccharose, human albumin, lactose, PVP or gelatin varieties.
- As long as the active ingredients are not incorporated in the liquid medicinal formulations in the form of a base, they are used in the form of their acid addition salts, hydrates or solvates in the preparations for parenteral use.
- A further systemic application form of importance is peroral administration as tablets, hard or soft gelatin capsules, coated tablets, powders, pellet, microcapsules, oblong compressives, granules, chewable tablets, lozenges, gums or sachets. These solid peroral administration forms can also be prepared as sustained action and/or depot systems. Among these are medicaments with an amount of one or more micronized active ingredients, diffusions and erosion forms based on matrices, for example by using fats, wax-like and/or polymeric compounds, or so-called reservoir systems. As a retarding agent and/or agent for controlled release, film or matrix forming substances, such as for example ethylcellulose, hydroxypropylmethylcellulose, poly(meth)acrylate derivatives (for example Eudragit®), hydroxypropylmethylcellulose phthalate are suitable in organic solutions as well as in the form of aqueous dispersions. In this connection, so-called bio-adhesive preparations are also to be named in which the increased retention time in the body is achieved by intensive contact with the mucus membranes of the body. An example of a bio-adhesive polymer is the group of Carbomers®.
- For sublingual application, compressives, such as for example non-disintegrating tablets in oblong form of a suitable size with a slow release of active ingredient, are especially suitable. For purposes of a targeted release of active ingredients in the various sections of the gastrointestinal tract, mixtures of pellets which release at the various places are employable, for example of gastric fluid soluble and small intestine soluble and/or gastric fluid resistant and large intestine soluble pellets. The same goal of releasing at various sections of the gastrointestinal tract can also be conceived by suitably produced laminated tablets with a core, whereby the coating of the agent is quickly released in gastric fluid and the core of the agent is slowly released in the small intestine milieu. The goal of controlled release at various sections of the gastrointestinal tract can also be attained by multilayer tablets. The pellet mixtures with differentially released agent can be filled into hard gelatin capsules.
- Anti-stick and lubricant and separating agents, dispersion agents such as flame dispersed silicone dioxide, disintegrants, such as various starch types, PVC, cellulose ester as granulating or retarding agents, such as for example wax-like and/or polymeric compounds on the basis of Eudragit®, cellulose or Cremophor® are used as a further adjuvants for the production of compressives, such as for example tablets or hard and soft gelatin capsules as well as coated tablets and granulates.
- Ant-oxidants, sweetening agents, such as for example saccharose, xylite or mannite, masking flavors, aromatics, preservatives, colorants, buffer substances direct tableting agents, such as for example microcrystalline cellulose, starch and starch hydrolystates (for example Celutab®), lactose, polyethylene glycols, polyvinylpyrrolidone and dicalcium phosphate, lubricants, fillers, such as lactose or starch, binding agents in the form of lactose, starch varieties, such as for example wheat or corn and/or rice starch, cellulose derivatives, for example methylcellulose, hydroxypropylcellulose or silica, talcum powder, stearates, such as for example magnesium stearate, aluminum stearate, calcium stearate, talc, siliconized talc, stearic acid, acetyl alcohol and hydrated fats are used.
- In this connection, oral therapeutic system constructed especially on osmotic principles, such as for example GIT (gastrointestinal therapeutic system) or OROS (oral osmotic system), are also to be mentioned.
- Effervescent tablets or tabs. both of which represent immediately drinkable instant medicinal forms which are quickly dissolved or suspended in water are among the perorally administratable compressives. Among the perorally administratable forms are also solutions, for example drops, juices and suspensions, which can be produced according to the above given method, and can still contain preservatives for increasing stability and optionally aromatics for reasons of easier intake, and colorants for better differentiation as well as antioxidants and/or vitamins and sweeteners such as sugar or artificial sweetening agents. This is also true for inspisated juices which are formulated with water before ingestion. Ion exchange resins in combination with one or more active ingredients are also to be mentioned for the production of liquid ingestable forms.
- A special release form consists in the preparation of so-called floating medicinal forms, for example based on tablets or pellets which develop gas after contact with body fluids and therefore float on the surface of the gastric fluid. Furthermore, so-called electronically controlled release systems can also be formulated by which active ingredient release can be selectively adjusted to individual needs.
- A further group of systemic administration and also optionally topically effective medicinal forms are represented by rectally applicable medicaments. Among these are suppositories and enema formulations. The enema formulations can be prepared based on tablets with aqueous solvents for producing this administration form. Rectal capsules can also be made available based on gelatin or other carriers.
- Hardened fat, such as for example Witepsol®, Massa Estarium®, Novata®, coconut fat, glycerol-gelatin masses, glycerol-soap-gels and polyethylene glycols are suitable as suppository bases.
- For long-term application with a systematic active ingredient release up to several weeks, pressed implants are suitable which are preferably formulated on the basis of so-called biodegradable polymers.
- As a further important group of systemically active medicaments, transdermal systems are also to be emphasized which distinguish themselves, as with the above-mentioned rectal forms, by circumventing the liver circulation system and/or liver metabolism. These plasters can be especially prepared as transdermal systems which are capable of releasing the active ingredient in a controlled manner over longer or shorter time periods based on different layers and/or mixtures of suitable adjuvants and carriers. Aside from suitable adjuvants and carriers such as solvents and polymeric components, for example based on Eudragit®, membrane infiltration increasing substances and/or permeation promoters, such as for example oleic acid, Azone®, adipinic acid derivatives, ethanol, urea, propylglycol are suitable in the production of transdermal systems of this type for the purpose of improved and/or accelerated penetration.
- As topically, locally or regionally administration medicaments, the following are suitable as special formulations: vaginally or genitally applicable emulsions, creams, foam tablets, depot implants, ovular or transurethral administration installation solutions. For opthalmological application, highly sterile eye ointments, solutions and/or drops or creams and emulsions are suitable.
- In the same manner, corresponding otological drops, ointments or creams can be designed for application to the ear. For both of the above-mentioned applications, the administration of semi-solid formulations, such as for example gels based on Carbopols® or other polymer compounds such as for example polyvinylpyrolidone and cellulose derivatives is also possible.
- For customary application to the skin or also to the mucus membrane, normal emulsions, gels, ointments, cream or mixed phase and/or amphiphilic emulsion systems (oil/water-water/oil mixed phase) as well as liposomes and transfersomes can be named. Sodium algenate as a gel builder for production of a suitable foundation or cellulose derivatives, such as for example guar or xanthene gum, inorganic gel builders, such as for example aluminum hydroxides or bentonites (so-called thixotropic gel builder), polyacrylic acid derivatives, such as for example Carbopol®, polyvinylpyrolidone, microcrystalline cellulose or carboxymethylcellulose are suitable as adjuvants and/or carriers. Furthermore, amphiphilic low and high molecular weight compounds as well as phospholipids are suitable. The gels can be present either as hydrogels based on water or as hydrophobic organogels, for example based on mixtures of low and high molecular paraffin hydrocarbons and vaseline.
- Anionic, cationic or neutral tensides can be employed as emulsifiers, for example alkalized soaps, methyl soaps, amine soaps, sulfonated compounds, cationic soaps, high fatty alcohols, partial fatty acid esters of sorbitan and polyoxyethylene sorbitan, for example lanette types, wool wax, lanolin, or other synthetic products for the production of oil/water and/or water/oil emulsions.
- Hydrophilic organogels can be formulated, for example, on the basis of high molecular polyethylene glycols. These gel-like forms are washable. Vaseline, natural or synthetic waxes, fatty acids, fatty alcohols, fatty acid esters, for example as mono-, di-, or triglycerides, paraffin oil or vegetable oils, hardened castor oil or coconut oil, pig fat, synthetic fats, for example based on acrylic, caprinic, lauric and stearic acid, such as for example Softisan® or triglyceride mixtures such as Miglyol® are employed as lipids in the form of at and/or oil and/or wax-like components for the production of ointments, creams or emulsions.
- Osmotically effective acids and bases, such as for example hydrochloric acid, citric acid, sodium hydroxide solution, potassium hydroxide solution, monosodium carbonate, further buffer systems, such as for example citrate, phosphate, Tris-buffer or triethanolamine are used for adjusting the pH value.
- Preservatives, for example such as methyl- or propyl benzoate parabenes) or sorbic acid can be added for increasing stability.
- Pastes, powders or solutions are to be mentioned as further topically applicable forms. Pastes often contain lipophilic and hydrophilic auxiliary agents with very high amounts of fatty matter as a consistency-giving base.
- Powders or topically applicable powders can contain for example starch varieties such as wheat or rice starch, flame dispersed silicon dioxide or silica, which also serve as diluents, for increasing flowability as well as lubricity as well as for preventing agglomerates.
- Nose drops or nose sprays serve as nasal application forms. In this connection, nebulizers or nose crams or ointments can come to use.
- Furthermore, nose spray or dry powder formulations as well as controlled dosage aerosols are also suitable for systemic administration of the active ingredients.
- These pressure and/or controlled dosage aerosols and dry powder formulations can be inhaled and/or insufflated. Administration forms of this type also certainly have importance for direct, regional application in the lung or bronchi and larynx. Thereby, the dry powder compositions can be formulated for example as active ingredient-soft pellets, as an active ingredient-pellet mixture with suitable carriers, such as for example lactose and/or glucose. For inhalation or insufflation, common applicators are suitable which are suitable for the treatment of the nose, mouth and/or pharynx. The active ingredients can also be applied by means of an ultrasonic nebulizing device. As a propellant gas for aerosol spray formulations and/or controlled dosage aerosols, tetrafluoroethane or HFC 134a and/or heptafluoropropane or HFC 227 are suitable, wherein non-fluorinated hydrocarbons or other propellants which are gaseous at normal pressure and room temperature, such as for example propane, butane or dimethyl ether can be preferred. Instead of controlled dosage aerosols, propellant-free, manual pump systems can also be used.
- The propellant gas aerosols can also suitably contain surface active adjuvants, such as for example isopropyl myristate, polyoxyethylene sorbitan fit acid ester, sorbitan trioleate, lecithins or soya lecithin.
- For regional application in situ, solutions for installation, for example for transurethral administration in bladder tumors or genital tumors, or for profusion in liver tumors or other organ carcinomas are suitable.
- The respective suitable medicinal forms can be produced in accordance with the prescription and procedures based on pharmaceutical-physical fundamentals as they are described for example in the following handbooks and are included in the present inventive subject-matter with respect to the production of the respective suitable medicaments:
- Physical Pharmacy (A. N. Martin, J. Swarbrick, A. Cammarata), 2nd Ed., Philadelphia Pa., (1970), German version: Physikalische Pharmazie, (1987), 3rd edition, Stuttgart;
- R. Voigt, M. Bornschein, Lehrbuch der pharmazeutischen Technologie, Verlag Chemie, Weinheim, (1984), 5th edition;
- P. H. List Arzneimformenlehre, Wissenschaftliche Verlagsgesellschaft mbH, Stuttgart, (1985), 4th edition;
- H. Sucker, P. Fuchs, P. Speiser, Pharmazeutische Technologie, Georg Thieme Verlag, Stuttgart-New York, (1991), 2nd edition;
- A. T. Florence, D. Attwood, Physicochemical Principles of Pharmacy, The Maximillan Press Ltd., Hong Kong, (1981);
- L. A. Trissel, Handbook on Injectable Drugs, American Society of Hospital Pharmacist, (1994), 8th edition;
- Y. W. Chien, Transdermal Controlled Systemic Medications, Marcel Dekker Inc., New York-Basel, (1987);
- K. E. Avis, L. Lachmann, H. A. Liebermann, Pharmaceutical Dosage Forms: Parenteral Medications, volume 2, Marcel Dekker Inc., New York-Basel, (1986);
- B. W. Müller, Controlled Drug Delivery, Paperback APV, volume 17, Wissenschaftliche Verlagsgesellschaft mbH, Stuttgart, (1987);
- H. Asch, D. Essig, P. C. Schmidt, Technologie von Salben, Suspensionen und Emulsionen, Wissenschaftliche Verlagsgesellschaft mbH, Stuggart, (1984);
- H. A. Liebermann, L. Lachman, J. B. Schwartz, Pharmaceutical Desage forms: Tablets, Volume 1, Marcel Dekker Inc., New York, 2nd Edition (1989);
- D. Chulin, M. Deleuil, Y. Pourcelot, Powder Technology and Pharmaceutical Processes, in J. C. Williams, T. Allen, Handbook of Powder Technology, Elsevier Amsterdam-London-New York-Tokyo, (1994);
- J. T. Carstensen, Pharmaceutical Principles of Solid Dosage Forms, Technomic Publishing Co., Inc., Lancaster-Basel, (1993).
- 1. Injection Therapeutics
- a) Parenteral Solution
active ingredient used according to the invention 5.000 g acid sodium phosphate 5.000 g sodium tartrate 12.000 g benzyl alcohol 7.500 g water for injection purposes to 1000.000 ml - The solution is produced according to the customary method, sterilized and filled into 10 ml vials. One vial contains 50 mg of the compound according to the invention.
- b) Penteral Solution
active ingredient used according to the invention 1.000 g hydrochloric acid, dilute 5.000 g sodium chloride 6.000 g water for injection purposes to 1000.000 ml - The solution is produced according to a customary method by stirring; the medicinal form is adjusted to a suitable pH value by acid addition and subsequently filled into 100 ml vials and sterilized. A vial contains 100 mg of the compound according to the invention.
- c) Parenteral Dispersion
active ingredient used according to the invention 10.000 g soya lecithin 20.000 g saturated triglycerides 100.000 g sodium hydroxide 7.650 g water for injection purposes to 1000.000 ml - The active ingredient(s) used according to the invention is dispersed in the saturated triglycerides. Then the soya lecithin is added under stirring, ad subsequent to this, the aqueous solution of sodium hydroxide is added with subsequent homogenization. The dispersion is sterilized and filled into 10 ml vials. A vial contains 50 mg of the compound according to the invention.
- d) Biodegradable Parenteral Depot Medicinal Form
active ingredient used according to the invention 10.000 polylactic acid /polygylcolic acid polymer 70.000 polyvinylpyrrolidone 0.200 gelatin 2.000 soya lecithin 2.000 isotonic sodium chloride solution to 1000.000 ml - First the active ingredient is incorporated into the biodegradable polymer comprising polylactic acid and polyglycolic acid by a suitable method (spray drying, solvent-evaporation or phase separation) and subsequently subjected to a sterilization process. The particles are introduced into a 2-chamber ready-made syringe in which the adjuvant solution, which is also produced in a sterile manner, is filled. The biodegradable microparticles are mixed with the dispersion agent shortly before application and dispersed. A ready-made syringe contains 200 mg of the active compound according to the invention.
- e) Parenteral Dispersion for Subcutaneous Installation
active ingredient used according to the invention 25,000 g soya lecithin 25,000 g arachis oil 400,000 g benzyl alcohol 50,000 g Miglyole ® to 1000,000 g - The active ingredient is dispersed together with soya lecithin and arachis oil. The benzyl alcohol is dissolved in Miglyole® and added to the dispersion. The entire dispersion is sterilized and subsequently filled into vials with 2 ml content A vial contains 50 mg active ingredient.
- f) Parenteral Perfusions Solution
- The solution named under example b) can also be used for perfusion of liver for example.
- According to need, inked of ampules with injection solution, so-called perforation bottles (vials), which can also be optionally preserved, and infusion solutions with an amount of one or more active ingredients according to the invention can also be made available in the customary manner under addition of buffer substances for adjustment of physiological pH value and/or the isotonicity and/or a best possible suitable pH value for the medicinal form (euhydria) and optional further required nutrients, vitamins, amino acids, stabilizers and other necessary adjuvants, possibly in combination with further medicinal agents suitable for the mentioned indications.
- 2. Solid, Peroral Administration Medicaments
- a) Tablets
active ingredient used according to the invention 10,000 g lactose 5,200 g starch, soluble 1,800 g hydroxypropylmethylcellulose 900 g magnesium stearate 100 g - The above components are mixed with each other and compacted in a conventional manner, wherein a tablet weight of ISO mg is set. Each tablet contains 100 mg active ingredient. If desired, the tablets obtained in this manner are coated, provided with a film coat and/or enterically coated.
- b) Coated Tablet Core
active ingredient used according to the invention 10,000 g flame dispersed silicon dioxide 500 g corn starch 2,250 g stearic acid 350 g ethanol 3.0 l gelatin 900 g purified water 10.0 l talcum 300 g magnesium stearate 180 g - From these components, a granulate is produced which is pressed to the desired coated tablet cores. Each core contains 50 mg of active ingredient. The core can be further processed in a customary manner to coated tablets. If desired, a gastric fluid resistant or retarding film coat can be applied in a known manner.
- c) Drink Suspension in Vials
active ingredient used according to the invention 0.050 g glycerin 0.500 g sorbits, 70% solution 0.500 g sodium saccharinate 0.010 g methyl-p-hydroxybenzoate 0.040 g aromatic agent q.s. sterile wasser q.s. to 5 ml - The above-mentioned components are mixed in a customary manner to a suspension and filled in a suitable drink vial having 5 ml content.
- d) Poorly Soluble Sublingual Tablets
active ingredient used according 0.030 g to the invention lactose 0.100 g stearic acid 0.100 g talcum purum 0.015 g sweetener q.s. aromatic agent q.s. rice starch q.s. to 0.500 g - The active ingredient is compacted together with the adjuvants under high pressure to sublingual tablets, favorably in oblong form.
- e) Soft Gel Capsule
active ingredient used according to the invention 0.050 g fatty acid glyceride mixture (Miglyole ®) q.s. to 0.500 g - The active ingredient is impasted together with the fluid carrier mixture and mixed together with further adjuvants suitable for the encapsulation and filled into elastic soft gelatin capsules which are sealed.
- f) Hard Gelatin Capsules
active ingredient used according to the invention 0.150 g microcrystalline cellulose 0.100 g hydroxypropylmethylcellulose 0.030 g mannite 0.100 g ethylcellulose 0.050 g triethyl citrate 0.010 g - The active ingredient is mixed together with the adjuvants, microcrystalline cellulose, hydroxypropylmethylcellulose and mannite, wet with granulation liquid and formed into pellets. These are subsequently coated with a solution of ethylcellulose and triethyl citrate in organic solvents in a fluidized-bed apparatus A hard gelatin capsule contains 150 mg of active ingredient.
- 3. Topically Administratable Medicinal Forms
- a) Hydrophilic Ointment
active ingredient used according to the invention 0.500 g Eucerinum ® anhydricum 60.000 g microcrystalline wax 15.000 g vaseline oil q.s. to 100.000 g - The above-mentioned adjuvants are melted and further processed together with the acetic ingredient to an ointment in a customary manner.
- b) Lipophilic Ointment
active ingredient used according to the invention 10.000 g propylene glycol 50.000 g paraffin, liquid 100.000 g paraffin wax 100.000 g vaseline to 1000.000 ml - The active ingredient(s) used according to the invention is dissolved in propylene glycol at ca. 60° C. At the same time, the lipophilic components are melted at 60-70° C. mad subsequently combined with the active ingredient solution. The ointment is emulsified at first at 60-70° C. and subsequently cooled to 35-40° C. under constant emulsification and then filled in 10 g tubes, A tube contains 100 mg of the compound according to the invention.
- 4. Inhalation Therapeutic
- Further subject-matter is a pharmaceutical formulation which is characterized in that it contains an active ingredient(s) used according to the invention as a base or a physiologically acceptable salt thereof together with carriers and/or diluents customary for this and suitable for administration by means of inhalation.
- In connection with the production of the medicaments, particularly suitable physiologically acceptable salts of the active ingredients are, as already illustrated in the synthesis section, acid addition salts derived from inorganic or organic acids such as for example especially hydrochloride, hydrobromide, sulfate, phosphate, maleate, tartrate, citrate, benzoate, 4-methoxybenzoate, 2- or 4-hydroxybenzoate, 4 chlorobenzoate, p-tosylate, methanesulfonate, ascorbate, salicylate, acetate, formate, succinate, lactate, glutarate, gluconate or tricarballylate.
- The administration of the active ingredient(s) used of the invention by means of inhalation occurs according to the invention in conventional ways customary for administrations of this form, for example in the form of a commercial controlled dosage aerosol or in combination with a spacer. In controlled dosage aerosols, a metering valve is delivered with whose help, a dosed amount of the composition is administered. For spraying, the present compositions can be formulated for example as aqueous solutions or suspensions and be administered by means of an atomizer. Aerosol spray formulations in which the active ingredient is either suspended with one or two stabilizers in a propellant as a carrier and/or diluent, for example tetrafluoroethane or HFC 134a and/or heptafluoropropane or HFC 227 can equally be used, whereby however, non-fluorinated hydrocarbons or other propellants which are gaseous at normal pressure and room temperature, such as propane, butane or dimethyl ether, can be preferred. Thereby, propellant-free manual pump system or dry powder systems as described below can also be used.
- Suitably, the propellant aerosols can also contain surface active adjuvants, such as for example isopropyl myristate, polyoxyethylene sorbitan fatty acid ester, sorbitan trioleate, lecithins, oleic acid.
- For administration by means of inhalation and/or insufflation, the medicaments with an amount of compounds according to the invention can also be formulated in the form of dry powder compositions, for example as active ingredient-soft pellets or as an active ingredient-powder mixture with a suitable carrier, such as for example lactose and/or glucose. The powder compositions can be formulated and administered as single doses or as multiple doses.
- The compounds according to the invention are preferably administered by means of a controlled dosage aerosol or in the form of a dry powder dosage formulation, wherein the latter preferably contains glucose and/or lactose as a carrier substance.
- As applicators for inhalation of the pharmaceutical formulations containing one or more of the active ingredient(s) used according to the invention, all applicators are generally suitable which are suitable for controlled dosage aerosols and/or a dry powder dosage formulation, such as for example usual applicators for the nose, mouth and or pharynx, or also devices standing under propellant gas for the delivery of a spray (as controlled dosage aerosol or dry powder dosage formulation) as they are also used for inhalations in the nose, mouth and/or pharynx.
- A further embodiment can also consist of an aqueous solution of the active ingredient(s) used according to the invention, which also optionally contains further active ingredients and/or additives, which are applied by means of an ultrasound atomizer.
- a) Controlled Dosage Aerosol
Intended dose per aerosol per stroke % by weight active ingredient used according 0.500 mg 0.66 to the invention stabilizer 0.075 mg 0.10 HFC 134a 75.500 mg 99.24 - b) Controlled Dosage Aerosol
Intended dose per aerosol per stroke % by weight active ingredient used according 0.250 mg 0.32 to the invention Stabilizer 0.038 mg 0.05 HFC 227 79.180 mg 99.63 - In the examples a) and b) the micronized active ingredient is, after previous dispersion in a small amount of the stabilizer, placed in a suspension vessel in which the bulk amount of propellant gas solution is found. The corresponding suspension is dispersed by means of a suitable stirring system (for example high performance mixer or ultrasound mixer) until an ultra-fine dispersion results. The suspension is then continuously held in flux in a filling apparatus suitable for cold propellants or pressure fillings. Alternatively, the suspension can also be produced in a suitable cooled stabilizer solution in HFC 134a/227.
- The examples c) to d) describe the composition and production of dosage dry powder formulations.
- c) Dosage-Dry Powder Formulation
mg/dose active ingredient used according to the invention 0.500 mg - d) Dosage-Dry Powder Formulation
mg/dose active ingredient used according to the invention 0.500 mg lactose Ph.Eur. to 2.5 mg or to 5.0 mg - e) Dosage-Dry Powder Formulation
mg/dose active ingredient used according to the invention 0.250 mg lactose Ph.Eur. to 2.5 mg or to 5.0 mg - In example c) the active ingredient is formulated after micronization under addition of stem as pellets with an MMAD between 0.1 and 0.3 mm diameter and brought to use in a multi-dose powder applicator.
- In the examples d) and e) the active ingredient is micronized, thereafter, bulk material is mixed with the lactose in the given amounts, and subsequently, filled in a multi-dose powder inhalator.
- In all of the examples set forth above, the active ingredient or the medicinal agent in the form of the respective suitable pharmaceutical acceptable salt and/or acid addition salts can be present, insofar as the base is not preferred in each case.
- In the following the pharmaceutical test results obtained in connection with the newly found indications based, in a representative manner, on the specifically structured new compounds are described.
- 1. Growth Inhibition of Human Tumor Cells
- The tumor growth inhibiting activity of the substances was determined on human tumor cells in standardized in vitro test systems. In the screening tests, the substances gave IC50-values in a concentration range of 0.1 nM to 10 μM.
- HepG2 cells plated at a density of 20,000 cells/ml in 12-well plastic dishes. Cultivation occurred in Richters IMEM-ZO nutrient medium with 5% fetal calf serum (FCS) in a tissue culture incubator with a gas mixture of 5% CO2 and 95% air at a temperature of 37° C. One day after plating, the culture medium was aspirated from the cells and replaced by fresh medium which contained the respective concentrations of the test substances. For the individual concentrations and the controls without test substances, three-fold batches were done for each. Three days after the beginning of treatment, the medium was again renewed with the test compounds. After six days of substance incubation, the test was added and the protein amount in the individual wells was determined with the sulforhodamine-B-method (according to P. Skehan et al.: New Colorimetric Cytotoxicity Assay for Anticancer-Drug Screening J. Natl. Cancer Inst. 82: 1107-1112, 1990). The IC50-values (defined as that concentration in which the cell growth was inhibited by 50%) was taken from the dose response curves and given as a comparative measurement for the activity of the test compounds.
- The following results were obtained:
Test substance No. IC50-value [μM] 136 0.002 153 0.002 159 0.0005 178 0.0007 199 0.001
2. Indications - The compounds of formula (I) and their salts permit a therapeutic use in malignant illness of humans and animals through their excellent inhibition of the growth of tumor cells. The anti-neoplastic activity of the described substances can be used for prophylactic, adjunct, palliative, and curative treatment of solid tumors, leukemic illnesses and lymphomas as well as for decreasing or preventing metastasis formation in humans and animals. The therapeutic use is possible in the following illnesses for example: gynecological tumors, such as of the uterus or the vagina, ovarian carcinomas, testicle tumors, prostate carcinomas, skin cancer, kidney cancer, bladder tumors, esophagus carcinomas, stomach cancer, rectal carcinomas, pancreas carcinomas, thyroid cancer, adrenal tumors, leukemia and lymphomas, Hodgkin's disease, tumor illnesses of the CNS, soft-tissue sarcomas, bone sarcomas, benign and malignant mesotheliomas, but especially intestine cancer, liver cancer, breast cancer, bronchial and lung carcinomas, melanomas, acute and chronic leukemias. Benign papillomatosis tumors are also considered for therapy with the named substances.
- The novel structural class of compounds possesses an independent activity profile in the effectiveness against the various tumor types. Thus, tumors which are resistant to customary cytostatic agents, for example, can respond entirely to these substances. In addition, based on the independent characteristics, combinations of the new compounds with known chemo-therapeutically used pharmaceuticals or other methods of treatment are considered as long as their properties are complimented in a suitable manner. The integration of the presently used compounds with their specific structures in a therapy scheme is successful with one or more substances from the following classes for example: anti-metabolites (for example cytarabine, 5-fluorouracil, 6 mercaptopurine, methotrexate), alkylating agents (for example busulfan, carmustine, cisplatin, carboplatin, cyclophosphamide, dacarbazine, melphalan, thiotepa), DNA-intercalating substances and topoisomerase inhibitors (for example actinomycin D, daunorubicin, doxorubicin, mitomycin C, mitoxantrone, etoposide, teniposide, topotecan, irinotecan), spindle poisons (for example vincristine, navelbine, taxol, taxotere), hormonally active agents (for example tamoxifen, flutamide, formestane, goserelin) or other cytostatic agents with complex modes of action (for example L-asparaginase, bleomycin, hydroxyurea). Resistant tumor cells can be made sensitive again by interaction of the new compounds with a mechanism of resistance for common cytostatic agents (for example P-glycoprotein, MRP, glutathione-S-transferase, metallothionein). A combination is also applicable with radiation therapy, hyperthermia or immunotherapy, for example.
- 3. Immuno Suppressing Activity
- Many anti-tumor agents have not only a cytotoxic effect on tumor cells, but also on the blood cell system. This leads to a weakening of the immune defense, which can, in turn, be specifically employed to suppress the rejection reaction after an organ transplantation for example. Therefore, a use of the main compounds, optionally in combination with other compounds effective for these indications is suitable in diseases such as psoriasis or autoimmune disease. In order to test the possibility for a therapeutic use in illnesses of this type, the substance activity was tested on freshly isolated lymphocytes as follows:
- The spleen of a Swiss mouse served as a lymphocyte source. The lymphocyte population was isolated from the spleen cell suspension over a ficoll gradient and taken up in IMEM-ZO culture medium with 0.1% dextran 70,000 and 2% fetal calf serum. The cells were plated at a density of CL 500,000-cells/well/ml in a 12-well plate, 1 ml doubly concentrate test substance solution was pipetted per well and this was subsequently incubated in a tissue culture incubator at 37° C. and 5% CO2. After 2 days, a 1 ml-aliquot with 5 μl of the fluorescent dye solutions propidium iodide (8 mg/ml) and 3,3′-dihexyloxacarbocyanin iodide (40 μg/ml) each was added per well, and incubated for 3 minutes at room temperature. Subsequently, 10,000 cells per each sample were measured on a flow-through cytometer and the percentage amount of vital cells in the population was determined. By means of the dose-response curves, IC50-values were calculated which were also employed in the following Tables for the characterization of the individual substances:
Test Substance No. IC50 [μM] 150 0.0002 153 0.00008 159 0.003 195 0.002 199 0.00004 - The independent class of the compounds used according to the invention also permits an efficient combination with known immunosuppressive agents such as for example cyclosporin A, tacrolimus, rapamycin, azathioprine and glucocorticoids.
- The invention is in no way limited to the present respective concretely named active ingredient concentrations, dosages, combinations with one or more other cytostatic agents, tumor inhibitors, cancerostatic agents, immunosuppressive agents or further medicinal agents suitable for the respective specific indications or the type of tumor to treated or immunological illness, etc.
Claims (41)
—(CH2)r—(CR13R14)s—R12 (G1)
—NR12R14
—SO2—(CH2)rR12 (G3)
—COR15 (G5)
—(CH2)r—(CR13R14)s—R12 (G1)
—NR12R14
—SO2—(CH2)rR12 (G3)
—COR15 (G5)
—(CH2)r—(CR13R14)s—R12 (G1)
—NR12R14
—SO2—(CH2)rR12 (G3),
—COR15 (G5)
—(CH2)r—(CR13R14)s—R12 (G1)
—NR12R14
—SO2—(CH2)rR12 (G3),
—COR1 (G5)
L-G (IV)
HO-G (V)
H—NR12R14 (VI)
O═C═N—R12 (VII).
L-R4 (VIII)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US11/635,157 US20070219197A1 (en) | 1996-06-20 | 2006-12-07 | Pyridyl alkene and pyridyl alkine- acid amides as cytostatics and immuno-suppressives |
Applications Claiming Priority (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE19624659.8 | 1996-06-20 | ||
DE19624659A DE19624659A1 (en) | 1996-06-20 | 1996-06-20 | New pyridylalkene and pyridylalkanoic acid amides |
PCT/EP1997/003245 WO1997048696A1 (en) | 1996-06-20 | 1997-06-20 | Pyridyl alkene- and pyridyl alkine- acid amides as cytostatics and immunosuppressives |
US24254099A | 1999-02-18 | 1999-02-18 | |
US10/213,952 US7241745B2 (en) | 1996-06-20 | 2002-08-05 | Pyridyl alkene and pyridyl alkine acid amides as cytostatics and immunosupressives |
US11/635,157 US20070219197A1 (en) | 1996-06-20 | 2006-12-07 | Pyridyl alkene and pyridyl alkine- acid amides as cytostatics and immuno-suppressives |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US10/213,952 Continuation US7241745B2 (en) | 1996-06-20 | 2002-08-05 | Pyridyl alkene and pyridyl alkine acid amides as cytostatics and immunosupressives |
Publications (1)
Publication Number | Publication Date |
---|---|
US20070219197A1 true US20070219197A1 (en) | 2007-09-20 |
Family
ID=7797501
Family Applications (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US10/213,952 Expired - Fee Related US7241745B2 (en) | 1996-06-20 | 2002-08-05 | Pyridyl alkene and pyridyl alkine acid amides as cytostatics and immunosupressives |
US11/635,157 Abandoned US20070219197A1 (en) | 1996-06-20 | 2006-12-07 | Pyridyl alkene and pyridyl alkine- acid amides as cytostatics and immuno-suppressives |
US11/678,980 Abandoned US20070142377A1 (en) | 1996-06-20 | 2007-02-26 | Pyridyl Alkene and Pyridyl Alkine-Acid Amides as Cytostatics and Immunosuppressives |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US10/213,952 Expired - Fee Related US7241745B2 (en) | 1996-06-20 | 2002-08-05 | Pyridyl alkene and pyridyl alkine acid amides as cytostatics and immunosupressives |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US11/678,980 Abandoned US20070142377A1 (en) | 1996-06-20 | 2007-02-26 | Pyridyl Alkene and Pyridyl Alkine-Acid Amides as Cytostatics and Immunosuppressives |
Country Status (20)
Country | Link |
---|---|
US (3) | US7241745B2 (en) |
EP (1) | EP0923570B1 (en) |
JP (1) | JP4225572B2 (en) |
CN (2) | CN1152032C (en) |
AT (1) | ATE224888T1 (en) |
AU (1) | AU736206B2 (en) |
BR (1) | BR9709823B1 (en) |
CA (1) | CA2257448C (en) |
CZ (1) | CZ291791B6 (en) |
DE (2) | DE19624659A1 (en) |
DK (1) | DK0923570T3 (en) |
ES (1) | ES2179351T3 (en) |
HK (1) | HK1021974A1 (en) |
HU (1) | HU225715B1 (en) |
IL (1) | IL127352A (en) |
PT (1) | PT923570E (en) |
RU (1) | RU2200734C2 (en) |
TR (1) | TR199802651T2 (en) |
WO (1) | WO1997048696A1 (en) |
ZA (1) | ZA975437B (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20070142377A1 (en) * | 1996-06-20 | 2007-06-21 | Elfi Biedermann | Pyridyl Alkene and Pyridyl Alkine-Acid Amides as Cytostatics and Immunosuppressives |
Families Citing this family (74)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE19756235A1 (en) * | 1997-12-17 | 1999-07-01 | Klinge Co Chem Pharm Fab | New piperidinyl-substituted pyridylalkane alkene and alkane carboxylic acid amides |
DE19756261A1 (en) * | 1997-12-17 | 1999-07-01 | Klinge Co Chem Pharm Fab | New aryl-substituted pyridylalkane, alkene and alkyarboxylic acid amides |
DE19756236A1 (en) * | 1997-12-17 | 1999-07-01 | Klinge Co Chem Pharm Fab | Novel piperazinyl-substituted pyridylalkane, alkene and alkyarboxylic acid amides |
DE19756212A1 (en) * | 1997-12-17 | 1999-07-01 | Klinge Co Chem Pharm Fab | New cyclic imide-substituted pyridylalkane, alkene and alkyarboxylic acid amides |
DE19818044A1 (en) * | 1998-04-22 | 1999-10-28 | Klinge Co Chem Pharm Fab | Reducing side effects or neutralizing action of carcinostatic or immunosuppressive agents, especially pyridine derivatives, using vitamin PP compounds, e.g. nicotinamide |
BR9915403A (en) * | 1998-11-17 | 2001-08-14 | Hoffmann La Roche | 4-aroyl-piperidin-ccr-3 iii receptor antagonists |
EP1031564A1 (en) | 1999-02-26 | 2000-08-30 | Klinge Pharma GmbH | Inhibitors of cellular nicotinamide mononucleotide formation and their use in cancer therapy |
US6432432B1 (en) | 1999-03-05 | 2002-08-13 | Arch Chemicals, Inc. | Chemical method of making a suspension, emulsion or dispersion of pyrithione particles |
CO5180550A1 (en) | 1999-04-19 | 2002-07-30 | Smithkline Beecham Corp | FAB I INHIBITORS |
CO5370679A1 (en) | 1999-06-01 | 2004-02-27 | Smithkline Beecham Corp | FAB INHIBITORS 1 |
CA2387016C (en) * | 1999-10-08 | 2010-09-28 | William H. Miller | Acrylamide derivatives as fab i inhibitors |
US6730684B1 (en) | 1999-10-08 | 2004-05-04 | Affinium Pharmaceuticals, Inc. | Fab I inhibitors |
US6762201B1 (en) | 1999-10-08 | 2004-07-13 | Affinium Pharmaceuticals, Inc. | Fab I inhibitors |
WO2003088897A2 (en) | 2001-04-06 | 2003-10-30 | Affinium Pharmaceuticals, Inc. | Fab i inhibitors |
EP1348434A1 (en) * | 2002-03-27 | 2003-10-01 | Fujisawa Deutschland GmbH | Use of pyridyl amides as inhibitors of angiogenesis |
PL377847A1 (en) | 2003-01-14 | 2006-02-20 | Arena Pharmaceuticals Inc. | 1,2,3-trisubstituted aryl and heteroaryl derivatives as modulators of metabolism and the prpphylaxis and treatment of disorders related thereto such as diabetes and hyperglycemia |
WO2006115509A2 (en) | 2004-06-24 | 2006-11-02 | Novartis Vaccines And Diagnostics Inc. | Small molecule immunopotentiators and assays for their detection |
DOP2006000010A (en) | 2005-01-10 | 2006-07-31 | Arena Pharm Inc | PROCEDURE TO PREPARE AROMATIC ETERES |
US20110045065A1 (en) * | 2005-07-11 | 2011-02-24 | Ashok Vasantray Vyas | Substance having antioxidant, geroprotective and anti-ischemic activity and method for the preparation thereof |
WO2007053499A2 (en) | 2005-11-01 | 2007-05-10 | Millennium Pharmaceuticals, Inc. | Compounds useful as antagonists of ccr2 |
WO2007053498A1 (en) | 2005-11-01 | 2007-05-10 | Millennium Pharmaceuticals, Inc. | Compounds useful as antagonists of ccr2 |
EP2054422B1 (en) | 2006-07-20 | 2017-06-14 | Debiopharm International SA | Acrylamide derivatives as fab i inhibitors |
WO2008026018A1 (en) | 2006-09-01 | 2008-03-06 | Topotarget Switzerland Sa | New method for the treatment of inflammatory diseases |
EP3255045A1 (en) | 2007-02-16 | 2017-12-13 | Debiopharm International SA | Salts, prodrugs and polymorphs of fab i inhibitors |
EP2098231A1 (en) | 2008-03-05 | 2009-09-09 | Topotarget Switzerland SA | Use of NAD formation inhibitors for the treatment of ischemia-reperfusion injury |
AU2009264273B2 (en) | 2008-06-24 | 2015-01-22 | Onxeo Dk, Branch Of Onxeo S.A., France | Squaric acid derivatives as inhibitors of the nicotinamide |
EP2342181A1 (en) | 2008-08-29 | 2011-07-13 | Topo Target A/S | Novel urea and thiourea derivatives |
US8426446B2 (en) | 2009-05-12 | 2013-04-23 | Beijing Shiqiao Biopharm Co. Ltd. | Acrylamide derivative and use thereof in manufacture of medicament |
JP2012533530A (en) | 2009-07-17 | 2012-12-27 | トポターゲット・アクティーゼルスカブ | A method for predicting the efficacy of nicotinic acid or its precursor or prodrug administration to reduce the severity of side effects of cancer treatment with nicotinamide phosphoribosyltransferase inhibitors |
WO2011121055A1 (en) | 2010-03-31 | 2011-10-06 | Topotarget A/S | Pyridinyl derivatives comprising a cyanoguanidine or squaric acid moiety |
RU2617424C2 (en) | 2010-09-03 | 2017-04-25 | ФОРМА ТиЭм, ЭлЭлСИ | Novel compounds and compositions for inhibiting nampt |
EP2611804A1 (en) | 2010-09-03 | 2013-07-10 | Forma TM, LLC. | Novel compounds and compositions for the inhibition of nampt |
KR20140020823A (en) | 2010-09-03 | 2014-02-19 | 포르마 티엠, 엘엘씨. | Guanidine compounds and compositions for the inhibition of nampt |
BR112013008100A2 (en) | 2010-09-22 | 2016-08-09 | Arena Pharm Inc | "gpr19 receptor modulators and the treatment of disorders related thereto." |
PL2621903T3 (en) * | 2010-09-29 | 2017-08-31 | Intervet International B.V. | N-heteroaryl compounds |
CA2817093A1 (en) | 2010-11-15 | 2012-05-24 | Abbvie Inc. | Nampt inhibitors |
TW201238950A (en) | 2010-11-15 | 2012-10-01 | Abbott Lab | NAMPT and rock inhibitors |
TW201245152A (en) * | 2011-05-04 | 2012-11-16 | Forma Tm Llc | Novel compounds and compositions for the inhibition of NAMPT |
JP5872027B2 (en) * | 2011-05-09 | 2016-03-01 | フォーマ ティーエム, エルエルシー. | Piperidine derivatives and compositions for inhibiting nicotinamide phosphoribosyltransferase (NAMPT) |
MX349712B (en) | 2011-07-29 | 2017-08-09 | Karyopharm Therapeutics Inc | Hydrazide containing nuclear transport modulators and uses thereof. |
DK3404027T3 (en) | 2012-05-09 | 2020-06-02 | Biogen Ma Inc | CELL NUCLEAR TRANSPORT MODULATORS AND APPLICATIONS THEREOF |
CA2873075A1 (en) | 2012-05-11 | 2013-07-14 | Abbvie Inc. | Nampt inhibitors |
US8975398B2 (en) | 2012-05-11 | 2015-03-10 | Abbvie Inc. | NAMPT inhibitors |
US9334264B2 (en) | 2012-05-11 | 2016-05-10 | Abbvie Inc. | NAMPT inhibitors |
US9193723B2 (en) | 2012-05-11 | 2015-11-24 | Abbvie Inc. | NAMPT inhibitors |
JP6085026B2 (en) | 2012-06-19 | 2017-02-22 | デビオファーム インターナショナル エスエーDebiopharm International Sa | (E) -N-methyl-N-((3-methylbenzofuran-2-yl) methyl) -3- (7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl ) Prodrug derivatives of acrylamide |
EP2925750A1 (en) | 2012-11-29 | 2015-10-07 | Karyopharm Therapeutics, Inc. | Substituted 2,3-dihydrobenzofuranyl compounds and uses thereof |
US10202366B2 (en) | 2013-03-15 | 2019-02-12 | Karyopharm Therapeutics Inc. | Methods of promoting wound healing using CRM1 inhibitors |
EP3492455B1 (en) | 2013-06-21 | 2023-05-17 | Karyopharm Therapeutics Inc. | 1,2,4-triazoles as nuclear transport modulators and use in the treatment of specific forms of cancer |
KR102581373B1 (en) | 2013-07-03 | 2023-09-20 | 카리오팜 쎄라퓨틱스, 인코포레이티드 | Substituted benzofuranyl and benzoxazolyl compounds and uses thereof |
WO2015042414A1 (en) | 2013-09-20 | 2015-03-26 | Karyopharm Therapeutics Inc. | Multicyclic compounds and methods of using same |
JP2016532648A (en) * | 2013-10-09 | 2016-10-20 | イーライ リリー アンド カンパニー | Novel pyridyloxyacetyl tetrahydroisoquinoline compounds useful as NAMPT inhibitors |
JP2017521426A (en) | 2014-07-23 | 2017-08-03 | オーリジーン ディスカバリー テクノロジーズ リミテッドAurigene Discovery Technologies Limited | 4,5-Dihydroisoxazole derivatives as NAMPT inhibitors |
MX2017002013A (en) | 2014-08-15 | 2017-05-12 | Karyopharm Therapeutics Inc | Polymorphs of selinexor. |
AU2016205361C1 (en) | 2015-01-06 | 2021-04-08 | Arena Pharmaceuticals, Inc. | Methods of treating conditions related to the S1P1 receptor |
CN104447486B (en) * | 2015-01-13 | 2016-06-01 | 佛山市赛维斯医药科技有限公司 | Diene fluoroadamantane compounds, Preparation Method And The Use |
CN104447484B (en) * | 2015-01-13 | 2016-06-08 | 佛山市赛维斯医药科技有限公司 | Containing alkoxyphenyl radical and the compound of diene adamantane structure, Preparation Method And The Use |
CN104447483B (en) * | 2015-01-13 | 2016-07-27 | 佛山市赛维斯医药科技有限公司 | Containing aniline and the compound of diene adamantane structure, Preparation Method And The Use |
SI3310760T1 (en) | 2015-06-22 | 2023-02-28 | Arena Pharmaceuticals, Inc. | Crystalline l-arginine salt of (r)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclo-penta(b)indol-3-yl)acetic acid for use in s1p1 receptor-associated disorders |
WO2017031323A1 (en) | 2015-08-18 | 2017-02-23 | Karyopharm Therapeutics Inc. | (s,e)-3-(6-aminopyridin-3-yl)-n-((5-(4-(3-fluoro-3-methylpyrrolidine-1-carbonyl)phenyl)-7-(4-fluorophenyl)benzofuran-2-yl)methyl)acrylamide for the treatment of cancer |
TW201720802A (en) * | 2015-09-15 | 2017-06-16 | 艾森伯利生物科學公司 | Hepatitis B core protein modulators |
US10858347B2 (en) | 2015-12-31 | 2020-12-08 | Karyopharm Therapeutics Inc. | Multicyclic compounds and uses thereof |
EP3397633A1 (en) | 2015-12-31 | 2018-11-07 | Karyopharm Therapeutics, Inc. | Nuclear transport modulators and uses thereof |
US10709706B2 (en) | 2015-12-31 | 2020-07-14 | Karopharm Therapeutics Inc. | Nuclear transport modulators and uses thereof |
US10751351B2 (en) | 2016-02-26 | 2020-08-25 | Debiopharm International S.A. | Medicament for treatment of diabetic foot infections |
EP3279192A1 (en) | 2016-08-05 | 2018-02-07 | Centre Hospitalier Universitaire Vaudois (CHUV) | Piperidine derivatives for use in the treatment of pancreatic cancer |
WO2018086703A1 (en) | 2016-11-11 | 2018-05-17 | Bayer Pharma Aktiengesellschaft | Dihydropyridazinones substituted with phenylureas |
WO2018098472A1 (en) | 2016-11-28 | 2018-05-31 | Karyopharm Therapeutics Inc. | Crm1 inhibitors for treating epilepsy |
CN107827897A (en) * | 2017-10-23 | 2018-03-23 | 青岛大学 | Synthesis method of chiral hepta-spiro indolone compound |
JP2021512103A (en) | 2018-01-31 | 2021-05-13 | バイエル アクチェンゲゼルシャフトBayer Aktiengesellschaft | Antibody drug conjugate (ADCS) containing a NAPPT inhibitor |
CN108558840B (en) * | 2018-06-04 | 2020-11-06 | 上海交通大学 | Water-soluble aza-alpha-naphthalene flavone compound and preparation method and medical application thereof |
WO2021013693A1 (en) | 2019-07-23 | 2021-01-28 | Bayer Pharma Aktiengesellschaft | Antibody drug conjugates (adcs) with nampt inhibitors |
BR112022008753A2 (en) | 2019-11-06 | 2022-07-19 | Remedy Plan Inc | CANCER TREATMENTS TARGETED TO CANCER STEM CELLS |
JP2024518089A (en) | 2021-05-13 | 2024-04-24 | リメディー プラン,インコーポレーテッド | NAMPT inhibitors and their uses |
Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4283541A (en) * | 1980-05-27 | 1981-08-11 | Usv Pharmaceutical Corporation | Pyridylacyl-hydroxamates |
US5169856A (en) * | 1988-02-15 | 1992-12-08 | Takeda Chemical Industries, Inc. | Piperidinoalkyl derivatives of carboxylic acid amides |
US5260323A (en) * | 1990-06-28 | 1993-11-09 | Hoechst Aktiengesellschaft | 2,4- and 2,5-substituted pyridine-N-oxides, processes for their preparation and their use |
US5326772A (en) * | 1984-09-28 | 1994-07-05 | Byk Gulden Lomberg Chemische Fabrik Gmbh | Diaryl compounds for their use |
US6444823B1 (en) * | 1996-06-20 | 2002-09-03 | Klinge Pharma Gmbh | Pyridyl alkane acid amides as cytostatics and immunosuppressives |
US7241745B2 (en) * | 1996-06-20 | 2007-07-10 | Astellas Pharma Gmbh | Pyridyl alkene and pyridyl alkine acid amides as cytostatics and immunosupressives |
Family Cites Families (30)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
NL8005133A (en) | 1980-09-12 | 1982-04-01 | Duphar Int Res | PHENYLPIPERAZINE DERIVATIVES WITH ANTIAGRESSIVE ACTION. |
US4778796A (en) | 1985-07-19 | 1988-10-18 | Dainippon Pharmaceutical Co., Ltd. | ω-(3-pyridyl)alkenamide derivatives and anti-allergenic pharmaceutical compositions containing same |
DE3641822A1 (en) | 1986-12-06 | 1988-06-16 | Goedecke Ag | USE OF DIHYDROPHENYLAMINOSAE DERIVATIVES AND MEDICINAL PRODUCTS CONTAINING THEM FOR IMMUNULATION AND CYTOSTASE |
JPS63179869A (en) | 1987-01-20 | 1988-07-23 | Dainippon Pharmaceut Co Ltd | Piperidine derivative |
HU206181B (en) | 1988-02-19 | 1992-09-28 | Byk Gulden Lomberg Chem Fab | Process for producing pharmaceutical compositions comprising optically pure r-(+)-niguldipin and its derivatives and suitable for treating tumoros diseases |
EP0343307A1 (en) * | 1988-05-26 | 1989-11-29 | Fabrica Espanola De Productos Quimicos Y Farmaceuticos, S.A. | 4-Piperidinealkanamine derivatives |
IE903196A1 (en) | 1989-09-05 | 1991-03-13 | Searle & Co | Substituted n-benzylpiperidine amides |
FI97540C (en) | 1989-11-06 | 1997-01-10 | Sanofi Sa | Process for the preparation of therapeutically useful aromatically substituted piperidine and piperazine derivatives |
WO1991015484A1 (en) | 1990-04-10 | 1991-10-17 | Byk Gulden Lomberg Chemische Fabrik Gmbh | Pyridines as medicaments |
JPH05506027A (en) | 1990-04-10 | 1993-09-02 | ビイク グルデン ロンベルク ヒエーミツシエ フアブリーク ゲゼルシヤフト ミツト ベシユレンクテル ハフツング | New pyridine ester |
DE4020570A1 (en) | 1990-06-28 | 1992-01-02 | Hoechst Ag | 2,4- AND 2,5-SUBSTITUTED PYRIDINE-N-OXIDES, METHOD FOR THE PRODUCTION AND USE THEREOF |
US5244908A (en) | 1990-07-30 | 1993-09-14 | Takeda Chemical Industries, Ltd. | Imidazopyridine derivatives and their pharmaceutical use |
EP0479601B1 (en) | 1990-10-05 | 1999-12-15 | Ajinomoto Co., Inc. | Piperidine derivatives and their use as antiarrhythmic agents |
FR2676053B1 (en) | 1991-05-03 | 1993-08-27 | Sanofi Elf | NOVEL DIALKYLENEPIPERIDINO COMPOUNDS AND THEIR ENANTIOMERS, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM. |
EP0522606B1 (en) | 1991-05-10 | 1996-04-03 | Takeda Chemical Industries, Ltd. | Pyridine derivatives, their production and use |
US5208247A (en) | 1991-08-01 | 1993-05-04 | American Cyanamid Company | Pyridinium compounds which are useful as antagonists of platelet activating factor |
CA2085954A1 (en) | 1991-12-24 | 1993-06-25 | Klaus Weidmann | Substituted pyridine n-oxides, processes for their preparation, and their use |
US5622976A (en) | 1991-12-31 | 1997-04-22 | Fujisawa Pharmaceutical Co., Ltd. | Oxadiazole derivatives having acetylcholinesterase-inhibitory and muscarinic agonist activity |
FR2686084B1 (en) | 1992-01-10 | 1995-12-22 | Bioprojet Soc Civ | NEW IMIDAZOLE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATIONS. |
GB9200535D0 (en) | 1992-01-10 | 1992-02-26 | Fujisawa Pharmaceutical Co | New compound |
US5612336A (en) | 1992-07-13 | 1997-03-18 | Merck, Sharp & Dohme Ltd. | Heterocyclic amide derivatives as tachykinin antagonists |
IL111235A (en) | 1993-10-15 | 2001-03-19 | Schering Plough Corp | Pharmaceutical compositions for inhibition of g-protein function and for treatment of proliferative diseases containing tricyclic compounds some such compounds and process for preparing part of them |
JP2875393B2 (en) | 1993-10-15 | 1999-03-31 | シェーリング コーポレイション | Tricyclic carbamate compounds useful for inhibiting G-protein function and treating proliferative disorders |
HUT76057A (en) | 1993-10-15 | 1997-06-30 | Schering Corp | Tricyclic sulfonamide compounds, pharmaceutical compositions containing them, which are useful for inhibition of g-protein function and for treatment of proliferative diseases and process for producing them |
WO1995024894A2 (en) | 1994-03-14 | 1995-09-21 | The Government Of The United States Of America, Represented By The Secretary, Department Of Health And Human Services | Use of lipoxygenase inhibitors as anti-cancer therapeutic and intervention agents |
IL117798A (en) | 1995-04-07 | 2001-11-25 | Schering Plough Corp | Tricyclic compounds useful for inhibition of g-protein function and for treatment of proliferative diseases and pharmaceutical compositions comprising them |
US5712280A (en) | 1995-04-07 | 1998-01-27 | Schering Corporation | Tricyclic compounds useful for inhibition of G-protein function and for treatment of proliferative diseases |
FR2738245B1 (en) | 1995-08-28 | 1997-11-21 | Sanofi Sa | NOVEL PIPERIDINE DERIVATIVES, PROCESS FOR THEIR PRODUCTION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM |
DE19624668A1 (en) | 1996-06-20 | 1998-02-19 | Klinge Co Chem Pharm Fab | Use of pyridylalkane, pyridylalken or pyridylalkynamides |
US6451816B1 (en) * | 1997-06-20 | 2002-09-17 | Klinge Pharma Gmbh | Use of pyridyl alkane, pyridyl alkene and/or pyridyl alkine acid amides in the treatment of tumors or for immunosuppression |
-
1996
- 1996-06-20 DE DE19624659A patent/DE19624659A1/en not_active Ceased
-
1997
- 1997-06-19 ZA ZA9705437A patent/ZA975437B/en unknown
- 1997-06-20 ES ES97928261T patent/ES2179351T3/en not_active Expired - Lifetime
- 1997-06-20 BR BRPI9709823-0B1A patent/BR9709823B1/en not_active IP Right Cessation
- 1997-06-20 CA CA002257448A patent/CA2257448C/en not_active Expired - Fee Related
- 1997-06-20 AU AU32625/97A patent/AU736206B2/en not_active Ceased
- 1997-06-20 IL IL12735297A patent/IL127352A/en not_active IP Right Cessation
- 1997-06-20 EP EP97928261A patent/EP0923570B1/en not_active Expired - Lifetime
- 1997-06-20 PT PT97928261T patent/PT923570E/en unknown
- 1997-06-20 JP JP50231898A patent/JP4225572B2/en not_active Expired - Fee Related
- 1997-06-20 DK DK97928261T patent/DK0923570T3/en active
- 1997-06-20 CN CNB971974241A patent/CN1152032C/en not_active Expired - Fee Related
- 1997-06-20 TR TR1998/02651T patent/TR199802651T2/en unknown
- 1997-06-20 AT AT97928261T patent/ATE224888T1/en active
- 1997-06-20 WO PCT/EP1997/003245 patent/WO1997048696A1/en active IP Right Grant
- 1997-06-20 HU HU9903766A patent/HU225715B1/en not_active IP Right Cessation
- 1997-06-20 DE DE69715888T patent/DE69715888T2/en not_active Expired - Lifetime
- 1997-06-20 RU RU99101069/04A patent/RU2200734C2/en not_active IP Right Cessation
- 1997-06-20 CN CNA2004100325866A patent/CN1546472A/en active Pending
- 1997-06-20 CZ CZ19984093A patent/CZ291791B6/en not_active IP Right Cessation
-
1999
- 1999-12-23 HK HK99106092A patent/HK1021974A1/en not_active IP Right Cessation
-
2002
- 2002-08-05 US US10/213,952 patent/US7241745B2/en not_active Expired - Fee Related
-
2006
- 2006-12-07 US US11/635,157 patent/US20070219197A1/en not_active Abandoned
-
2007
- 2007-02-26 US US11/678,980 patent/US20070142377A1/en not_active Abandoned
Patent Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4283541A (en) * | 1980-05-27 | 1981-08-11 | Usv Pharmaceutical Corporation | Pyridylacyl-hydroxamates |
US5326772A (en) * | 1984-09-28 | 1994-07-05 | Byk Gulden Lomberg Chemische Fabrik Gmbh | Diaryl compounds for their use |
US5169856A (en) * | 1988-02-15 | 1992-12-08 | Takeda Chemical Industries, Inc. | Piperidinoalkyl derivatives of carboxylic acid amides |
US5260323A (en) * | 1990-06-28 | 1993-11-09 | Hoechst Aktiengesellschaft | 2,4- and 2,5-substituted pyridine-N-oxides, processes for their preparation and their use |
US6444823B1 (en) * | 1996-06-20 | 2002-09-03 | Klinge Pharma Gmbh | Pyridyl alkane acid amides as cytostatics and immunosuppressives |
US7241745B2 (en) * | 1996-06-20 | 2007-07-10 | Astellas Pharma Gmbh | Pyridyl alkene and pyridyl alkine acid amides as cytostatics and immunosupressives |
US7276524B2 (en) * | 1996-06-20 | 2007-10-02 | Astellas Deutschland Gmbh | Pyridyl alkane acid amides as cytostatics and immunosuppressives |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20070142377A1 (en) * | 1996-06-20 | 2007-06-21 | Elfi Biedermann | Pyridyl Alkene and Pyridyl Alkine-Acid Amides as Cytostatics and Immunosuppressives |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US7241745B2 (en) | Pyridyl alkene and pyridyl alkine acid amides as cytostatics and immunosupressives | |
EP0912176B1 (en) | Use of pyridyl alkane, pyridyl alkene and/or pyridyl alkine acid amides in the treatment of tumors or for immunosuppression | |
EP1060163B1 (en) | New piperazinyl-substituted pyridylalkane, alkene and alkine carboxamides | |
US6451816B1 (en) | Use of pyridyl alkane, pyridyl alkene and/or pyridyl alkine acid amides in the treatment of tumors or for immunosuppression | |
US6903118B1 (en) | Piperazinyl-substituted pyridylalkane, alkene and alkine carboxamides | |
US6444823B1 (en) | Pyridyl alkane acid amides as cytostatics and immunosuppressives | |
US6593344B1 (en) | Piperadinyl-substituted pyridylalkane, alkene and alkine carboxamides | |
US7320993B1 (en) | Aryl-substituted pyridylalkane, alkene, and alkine carboxamides useful as cytostatic useful as cytostatic and immuosuppressive agents | |
KR100478405B1 (en) | Pyridylalkene- and pyridylalkyne-acidamides as cytostatic and immunosuppressive agents |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AS | Assignment |
Owner name: FUJISAWA DEUTSCHLAND GMBH, GERMANY Free format text: CHANGE OF NAME;ASSIGNOR:KLINGE PHARMA GMBH;REEL/FRAME:018691/0347 Effective date: 20020102 Owner name: ASTELLAS PHARMA GMBH, GERMANY Free format text: CHANGE OF NAME;ASSIGNOR:FUJISAWA GMBH;REEL/FRAME:018691/0460 Effective date: 20050620 |
|
AS | Assignment |
Owner name: ASTELLAS DEUTSCHLAND GMBH, GERMANY Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:ASTELLAS PHARMA GMBH;REEL/FRAME:019448/0083 Effective date: 20070514 |
|
STCB | Information on status: application discontinuation |
Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION |