WO2004032933A1 - Methode permettant de traiter le cancer - Google Patents
Methode permettant de traiter le cancer Download PDFInfo
- Publication number
- WO2004032933A1 WO2004032933A1 PCT/JP2003/013048 JP0313048W WO2004032933A1 WO 2004032933 A1 WO2004032933 A1 WO 2004032933A1 JP 0313048 W JP0313048 W JP 0313048W WO 2004032933 A1 WO2004032933 A1 WO 2004032933A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- group
- trimethoxyphenyl
- pyridine
- methyl
- production example
- Prior art date
Links
- 206010028980 Neoplasm Diseases 0.000 title claims abstract description 30
- 201000011510 cancer Diseases 0.000 title claims abstract description 26
- 238000000034 method Methods 0.000 title claims description 27
- 125000005809 3,4,5-trimethoxyphenyl group Chemical group [H]C1=C(OC([H])([H])[H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1* 0.000 claims abstract description 209
- -1 cyclic diamine compounds Chemical class 0.000 claims abstract description 195
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 29
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims abstract description 25
- 239000002253 acid Substances 0.000 claims abstract description 22
- 150000003839 salts Chemical class 0.000 claims abstract description 21
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 9
- 239000001257 hydrogen Substances 0.000 claims abstract description 7
- 239000004480 active ingredient Substances 0.000 claims abstract description 4
- 229940126585 therapeutic drug Drugs 0.000 claims abstract 2
- 238000004519 manufacturing process Methods 0.000 claims description 255
- 125000005843 halogen group Chemical group 0.000 claims description 20
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 14
- 125000003545 alkoxy group Chemical group 0.000 claims description 12
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 12
- 239000003814 drug Substances 0.000 claims description 9
- 229940124597 therapeutic agent Drugs 0.000 claims description 9
- 239000012830 cancer therapeutic Substances 0.000 claims description 5
- 125000001624 naphthyl group Chemical group 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- 125000005242 carbamoyl alkyl group Chemical group 0.000 claims description 4
- 125000004446 heteroarylalkyl group Chemical group 0.000 claims description 4
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 4
- 125000004103 aminoalkyl group Chemical group 0.000 claims description 3
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 3
- 229910052799 carbon Inorganic materials 0.000 claims description 3
- 125000004181 carboxyalkyl group Chemical group 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 125000002795 guanidino group Chemical group C(N)(=N)N* 0.000 claims description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 3
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims 1
- 102000013566 Plasminogen Human genes 0.000 claims 1
- 108010051456 Plasminogen Proteins 0.000 claims 1
- 125000004429 atom Chemical group 0.000 claims 1
- 239000003560 cancer drug Substances 0.000 claims 1
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims 1
- ZRALSGWEFCBTJO-UHFFFAOYSA-O guanidinium Chemical compound NC(N)=[NH2+] ZRALSGWEFCBTJO-UHFFFAOYSA-O 0.000 claims 1
- 239000008194 pharmaceutical composition Substances 0.000 claims 1
- 150000004677 hydrates Chemical class 0.000 abstract 1
- 150000001875 compounds Chemical class 0.000 description 286
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 213
- 238000003786 synthesis reaction Methods 0.000 description 209
- 230000015572 biosynthetic process Effects 0.000 description 201
- 238000005481 NMR spectroscopy Methods 0.000 description 141
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 114
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 100
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 73
- 239000000203 mixture Substances 0.000 description 68
- 230000002829 reductive effect Effects 0.000 description 67
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 66
- 239000012458 free base Substances 0.000 description 63
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 56
- 238000006243 chemical reaction Methods 0.000 description 53
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 50
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 49
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 48
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 47
- 239000000243 solution Substances 0.000 description 46
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 44
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 42
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 40
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 39
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 38
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 34
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 33
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 30
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 30
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 29
- 238000010898 silica gel chromatography Methods 0.000 description 29
- 229960001701 chloroform Drugs 0.000 description 28
- 238000005160 1H NMR spectroscopy Methods 0.000 description 25
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 25
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 23
- 229910052757 nitrogen Inorganic materials 0.000 description 22
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 21
- 239000012044 organic layer Substances 0.000 description 21
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 20
- 235000002639 sodium chloride Nutrition 0.000 description 20
- 150000002688 maleic acid derivatives Chemical class 0.000 description 19
- CNNWNFBHIQNIPW-UHFFFAOYSA-N 1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperazine Chemical compound COC1=C(OC)C(OC)=CC(C=2N=CC=C(CN3CCNCC3)C=2)=C1 CNNWNFBHIQNIPW-UHFFFAOYSA-N 0.000 description 18
- 238000002360 preparation method Methods 0.000 description 17
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 16
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 14
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 14
- 239000002904 solvent Substances 0.000 description 14
- 238000003756 stirring Methods 0.000 description 14
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 12
- 229920006395 saturated elastomer Polymers 0.000 description 12
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 11
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 10
- 238000001816 cooling Methods 0.000 description 10
- TWBYWOBDOCUKOW-UHFFFAOYSA-M isonicotinate Chemical compound [O-]C(=O)C1=CC=NC=C1 TWBYWOBDOCUKOW-UHFFFAOYSA-M 0.000 description 10
- 238000000746 purification Methods 0.000 description 10
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 10
- 235000017557 sodium bicarbonate Nutrition 0.000 description 10
- HXITXNWTGFUOAU-UHFFFAOYSA-N dihydroxy-phenylborane Natural products OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 description 9
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 9
- VZSRBBMJRBPUNF-UHFFFAOYSA-N 2-(2,3-dihydro-1H-inden-2-ylamino)-N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]pyrimidine-5-carboxamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C(=O)NCCC(N1CC2=C(CC1)NN=N2)=O VZSRBBMJRBPUNF-UHFFFAOYSA-N 0.000 description 8
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 8
- 150000001412 amines Chemical class 0.000 description 8
- 239000000706 filtrate Substances 0.000 description 8
- BEBCJVAWIBVWNZ-UHFFFAOYSA-N glycinamide Chemical compound NCC(N)=O BEBCJVAWIBVWNZ-UHFFFAOYSA-N 0.000 description 8
- WVDDGKGOMKODPV-UHFFFAOYSA-N hydroxymethyl benzene Natural products OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 8
- 239000012280 lithium aluminium hydride Substances 0.000 description 8
- 229910000027 potassium carbonate Inorganic materials 0.000 description 8
- 238000010992 reflux Methods 0.000 description 8
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 8
- RULQUTYJXDLRFL-UHFFFAOYSA-N (3,4,5-trimethoxyphenyl)boronic acid Chemical compound COC1=CC(B(O)O)=CC(OC)=C1OC RULQUTYJXDLRFL-UHFFFAOYSA-N 0.000 description 7
- 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 7
- MTZQAGJQAFMTAQ-UHFFFAOYSA-N benzoic acid ethyl ester Natural products CCOC(=O)C1=CC=CC=C1 MTZQAGJQAFMTAQ-UHFFFAOYSA-N 0.000 description 7
- 125000000319 biphenyl-4-yl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 7
- 238000007796 conventional method Methods 0.000 description 7
- SEGWFGBGQPUZSD-UHFFFAOYSA-N ethyl 2-ethylpyridine-4-carboxylate Chemical compound CCOC(=O)C1=CC=NC(CC)=C1 SEGWFGBGQPUZSD-UHFFFAOYSA-N 0.000 description 7
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 7
- IWELDVXSEVIIGI-UHFFFAOYSA-N piperazin-2-one Chemical compound O=C1CNCCN1 IWELDVXSEVIIGI-UHFFFAOYSA-N 0.000 description 7
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 239000012300 argon atmosphere Substances 0.000 description 6
- 239000006227 byproduct Substances 0.000 description 6
- 239000000796 flavoring agent Substances 0.000 description 6
- 235000013355 food flavoring agent Nutrition 0.000 description 6
- 238000002347 injection Methods 0.000 description 6
- 239000007924 injection Substances 0.000 description 6
- KQSSATDQUYCRGS-UHFFFAOYSA-N methyl glycinate Chemical compound COC(=O)CN KQSSATDQUYCRGS-UHFFFAOYSA-N 0.000 description 6
- 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 6
- XDEHMKQLKPZERH-BYPYZUCNSA-N (2s)-2-amino-3-methylbutanamide Chemical compound CC(C)[C@H](N)C(N)=O XDEHMKQLKPZERH-BYPYZUCNSA-N 0.000 description 5
- 229920002472 Starch Polymers 0.000 description 5
- 239000002246 antineoplastic agent Substances 0.000 description 5
- 239000002585 base Substances 0.000 description 5
- 210000004027 cell Anatomy 0.000 description 5
- 150000004985 diamines Chemical class 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- 238000009472 formulation Methods 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 5
- 239000012453 solvate Substances 0.000 description 5
- 239000003381 stabilizer Substances 0.000 description 5
- 239000008107 starch Substances 0.000 description 5
- 235000019698 starch Nutrition 0.000 description 5
- KZEVSDGEBAJOTK-UHFFFAOYSA-N 1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)-2-[5-[2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidin-5-yl]-1,3,4-oxadiazol-2-yl]ethanone Chemical compound N1N=NC=2CN(CCC=21)C(CC=1OC(=NN=1)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)=O KZEVSDGEBAJOTK-UHFFFAOYSA-N 0.000 description 4
- OKWNDHFPWXJEHM-UHFFFAOYSA-N 2-(3,4,5-trimethoxyphenyl)pyridine Chemical compound COC1=C(OC)C(OC)=CC(C=2N=CC=CC=2)=C1 OKWNDHFPWXJEHM-UHFFFAOYSA-N 0.000 description 4
- OPHQOIGEOHXOGX-UHFFFAOYSA-N 3,4,5-trimethoxybenzaldehyde Chemical compound COC1=CC(C=O)=CC(OC)=C1OC OPHQOIGEOHXOGX-UHFFFAOYSA-N 0.000 description 4
- VTCDZPUMZAZMSB-UHFFFAOYSA-N 3,4,5-trimethoxyphenol Chemical compound COC1=CC(O)=CC(OC)=C1OC VTCDZPUMZAZMSB-UHFFFAOYSA-N 0.000 description 4
- IBRWTCISGCXHQZ-UHFFFAOYSA-N 3-(3,4,5-trimethoxyphenyl)propan-1-ol Chemical compound COC1=CC(CCCO)=CC(OC)=C1OC IBRWTCISGCXHQZ-UHFFFAOYSA-N 0.000 description 4
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 4
- 206010006187 Breast cancer Diseases 0.000 description 4
- 208000026310 Breast neoplasm Diseases 0.000 description 4
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- 201000009030 Carcinoma Diseases 0.000 description 4
- 239000004471 Glycine Substances 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 4
- 229940024606 amino acid Drugs 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 229910052786 argon Inorganic materials 0.000 description 4
- 239000000872 buffer Substances 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 235000008504 concentrate Nutrition 0.000 description 4
- 239000012141 concentrate Substances 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- ULOLIZHBYWAICY-UHFFFAOYSA-N ethyl 2-(benzylamino)acetate Chemical compound CCOC(=O)CNCC1=CC=CC=C1 ULOLIZHBYWAICY-UHFFFAOYSA-N 0.000 description 4
- 229940064982 ethylnicotinate Drugs 0.000 description 4
- 239000012535 impurity Substances 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 4
- 210000003127 knee Anatomy 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 4
- 235000001968 nicotinic acid Nutrition 0.000 description 4
- 239000011664 nicotinic acid Substances 0.000 description 4
- XBLVHTDFJBKJLG-UHFFFAOYSA-N nicotinic acid ethyl ester Natural products CCOC(=O)C1=CC=CN=C1 XBLVHTDFJBKJLG-UHFFFAOYSA-N 0.000 description 4
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 4
- WEYVCQFUGFRXOM-UHFFFAOYSA-N perazine Chemical compound C1CN(C)CCN1CCCN1C2=CC=CC=C2SC2=CC=CC=C21 WEYVCQFUGFRXOM-UHFFFAOYSA-N 0.000 description 4
- 229960002195 perazine Drugs 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- 239000011780 sodium chloride Substances 0.000 description 4
- 125000001680 trimethoxyphenyl group Chemical group 0.000 description 4
- RDJUHLUBPADHNP-UHFFFAOYSA-N 1,2,3,5-tetrahydroxybenzene Chemical compound OC1=CC(O)=C(O)C(O)=C1 RDJUHLUBPADHNP-UHFFFAOYSA-N 0.000 description 3
- 125000003762 3,4-dimethoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1* 0.000 description 3
- BYHQTRFJOGIQAO-GOSISDBHSA-N 3-(4-bromophenyl)-8-[(2R)-2-hydroxypropyl]-1-[(3-methoxyphenyl)methyl]-1,3,8-triazaspiro[4.5]decan-2-one Chemical compound C[C@H](CN1CCC2(CC1)CN(C(=O)N2CC3=CC(=CC=C3)OC)C4=CC=C(C=C4)Br)O BYHQTRFJOGIQAO-GOSISDBHSA-N 0.000 description 3
- SBGHNDCBGPREJJ-UHFFFAOYSA-N 4-(chloromethyl)-2-(3,4,5-trimethoxyphenyl)pyridine Chemical compound COC1=C(OC)C(OC)=CC(C=2N=CC=C(CCl)C=2)=C1 SBGHNDCBGPREJJ-UHFFFAOYSA-N 0.000 description 3
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 3
- DRVDQUYTYFCSRR-UHFFFAOYSA-N 5-[3-(chloromethyl)phenyl]-1,2,3-trimethoxybenzene Chemical compound COC1=C(OC)C(OC)=CC(C=2C=C(CCl)C=CC=2)=C1 DRVDQUYTYFCSRR-UHFFFAOYSA-N 0.000 description 3
- OXGRBLMFIZTYMR-UHFFFAOYSA-N C(C1=CC=NC=C1)(=O)OCCCl Chemical compound C(C1=CC=NC=C1)(=O)OCCCl OXGRBLMFIZTYMR-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 3
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 3
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Classifications
-
- 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
- C07D213/36—Radicals substituted by singly-bound nitrogen atoms
- C07D213/38—Radicals substituted by singly-bound nitrogen atoms having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Definitions
- the present invention relates to novel cancer therapeutics and methods.
- the present inventors have searched for a substance having an inhibitory effect on cancer cell growth by using a cultured cell system.
- the group of compounds represented by the general formula (1) described below has been identified as an excellent cancer
- the present inventor has found that it has a cell growth inhibitory effect and is useful as a therapeutic agent for cancer, and has completed the present invention.
- a 2 represents one CH 2 —, one CH 2 CH 2 —, one CO— or _CH (CH 3 ) —;
- R 1 represents hydrogen
- R 2 represents a hydrogen atom, an alkyl group, a hydroxyalkyl group, an arylalkyl group, a heteroarylalkyl group, a carboxyalkyl group, a carbamoylalkyl group, an aminoalkyl group or a guanidino atom;
- Z represents an alkyl group;
- Z represents the formula (2) or (3)
- R 3 , RRR 7 and R 8 are the same or different and represent a hydrogen atom, an alkyl group, an alkoxy group, a halogen atom, or a nitro group;
- R 5 is a hydrogen atom, an alkyl group, an alkoxy group, a halogen atom , A nitro group, a naphthyl group, or an alkyl group, an alkoxy group, a halogen atom, a nitro group and a phenyl group which may be substituted by 1 to 3 groups;
- R 1 and R 2 are both hydrogen atoms, Z is not a 3,4,5-trimethoxyphenyl group! /. ]
- a method for treating cancer which comprises administering an effective amount of the cyclic diamine compound represented by the formula (I), an acid addition salt thereof or a hydrate thereof.
- the present invention also provides a therapeutic agent for cancer comprising the above cyclic diamine compound, its acid salt or a hydrate thereof as an active ingredient.
- the present invention provides the above-mentioned cyclic diamine compound, and an acid thereof; ] It is intended to provide a medicament or composition for cancer treatment, comprising a mouth salt or a hydrate thereof, and a pharmaceutically acceptable carrier.
- the present invention provides the use of the above-mentioned cyclic diamine compound, an acid addition salt thereof or a hydrate thereof for producing a therapeutic agent for cancer.
- a C! -C 6 -alkyl group is preferable.
- a hydroxy C i — C 6 -alkyl group is preferable, and specific examples thereof include a hydroxymethyl group, a 2-hydroxyethyl group, a 2-hydroxy-1-methylethyl group, and a 2-hydroxyethyl group.
- Particularly preferred are a hydroxymethyl group, a 2-hydroxylethyl group, a 2-hydroxyl-1-methylethyl group, a 2-hydroxy-11,1-dimethylethyl group, and a 3-hydroxypropyl group.
- An aryl C 1 -C 6 -alkyl group is preferred, and specific examples include phenyl CJ-C 6 -alkyl groups such as a benzyl group and a phenethyl group.
- phenyl CJ-C 6 -alkyl groups such as a benzyl group and a phenethyl group.
- heteroarylalkyl group a 5- or 6-membered heteroaryl-1-C 6 -alkyl group having 1 or 2 nitrogen atoms as a hetero atom is preferable. More preferably pyridyl-C, 1C W
- alkyl group pyridinium Mijiru one C, - C 6 - alkyl group, imidazolyl one C "c 6 - alkyl group, pyrrolyl one d-c 6 -.
- the alkyl group and the like Karubokishiaru kill group, carboxy one A Ci—Ce-alkyl group is preferred, and specific examples thereof include a carboxymethyl group, a carboxyl group, etc.
- carbamoylalkyl group a carbamoyl-1-C 6 -alkyl group is preferred.
- Cal Bamoirumechiru group is a force Rubamoiruechiru group, and the like amino group-amino C one C 6 -.!.
- the guanidinoalkyl group is preferably a guanidino 1 d-c 6 -alkyl group, and specifically, a guanidinomethyl group, Examples include a nidinoethyl group and a guanidinopropyl group.
- (CH 2) n methylene, ethylene and trimethylene styrene is preferred.
- CO (CH 2 ) n is preferably CO 2 COCH 2 .
- a 2 represents CH 2 , CH 2 CH 2 , CO or CH (CH 3 ), with CH 2 and CH 2 CH 2 being particularly preferred.
- a C! -Ce-alkyl group is preferable, and specifically, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a tert group
- examples thereof include a monobutyl group, a pentyl group, and a hexyl group, and a methyl group, an ethyl group, an n-propyl group, an isopropyl group, and a tert-butyl group are particularly preferable.
- a C 6 -alkoxy group is preferable, and specific examples include a methoxy group, an ethoxy group, an isopropoxy group, an n-butoxy group, and an isobutoxy group. Particularly, a methoxy group, an ethoxy group and an isopropoxy group are preferred.
- halogen atom represented by R 3 to R 8 a chlorine atom, a bromine atom, Examples include a fluorine atom and an iodine atom.
- R 5 may be a fuel group which may be substituted by 1 to 3 groups selected from an alkyl group, an alkoxy group, a halogen atom, a nitro group and a phenyl group, and the substituent on the phenyl group
- alkyl group, the alkoxy group, and the halogen atom are the same as those described above.
- the ring having X and Y in the formula (2) includes a benzene ring, a pyridine ring and a pyrimidine ring.
- Z is not a 3,4,5-trimethoxyphenyl group.
- the acid addition salt of the compound (1) is not particularly limited as long as it is a pharmaceutically acceptable salt, and examples thereof include hydrochloride, hydrobromide, hydroiodide, sulfate, and phosphate.
- acid addition salts of organic acids such as citrate and acetate.
- the compound (1) may exist in the form of a solvate represented by a hydrate, and the solvate is also included in the present invention.
- the compound (1) can be produced, for example, according to the following methods a to f.
- R 9 represents a halogen atom, an alkylsulfonyloxy group or an arylsulfonyloxy group
- R ′, R 2 , A 2 and Z are the same as above
- ethyl 2-ethyl isonicotinate (4) was converted to 3,4,5-trimethoxyphenylboronic acid (5) at 0 ° C.
- the compound (6) is obtained by reacting at a reflux temperature, preferably 90 ° C., for 10 minutes to several days, preferably overnight. It is preferably mixed with lithium aluminum hydride in THF at room temperature above 20 ° C, preferably at 0 ° C for several minutes to several hours. Or by reacting for 30 minutes to give the alcohol (7).
- Alcohol (7) is treated with thionyl chloride in a solvent such as chlorophonolem, dichloromethane, ethyl acetate, ether, THF, dioxane or the like at room temperature above -20 ° C, preferably at 0 ° C for 1 hour to several days, preferably 5 hours.
- Chlorine (8) is obtained by stirring for an hour.
- the chloro form (8) and the diamine form (9) were converted from room temperature to 100 ° C. in the presence of carbon dioxide in a solvent such as N, N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), or acetonitrile.
- a solvent such as chlorophonolem, dichloromethane, ethyl acetate, ether, THF, dioxane or the like
- Chlorine (8) is obtained by stirring for an hour.
- the chloro form (8) and the diamine form (9) were converted from room temperature to 100 ° C. in
- the monosubstituted product (10) is obtained by stirring at room temperature for preferably 1 hour to several days, preferably for 5 hours.
- the compound (la) is obtained by condensing the compound (10) with the compound (11).
- the condensation reaction is carried out by stirring in a solvent such as DMF, DMSO, and acetonitrile at room temperature to 100 ° C, preferably 70 ° C for 1 hour to several days, preferably 2 hours, in the presence of potassium carbonate.
- the halogen atom represented by R 9 is preferably a chlorine atom or a bromine atom.
- the alkylsulfonyloxy group is preferably a methanesulfonyloxy group, and the arylsulfonyloxy group is preferably a p-toluenesulfonyloxy group.
- the compound (11) is produced, for example, according to the following reaction formula.
- R 1Q represents a hydrogen atom or a lower alkyl group
- a la is (CH 2 ).
- (CH 2 ) n CH CH, and Z and R 9 are the same as above]
- the carboxylic acid compound or its ester derivative (12) is reduced using a reducing agent such as lithium aluminum hydride to obtain an alcohol compound (13).
- the compound (11) is obtained by reacting a halogenating agent such as thionyl chloride with a methanesulfonylating agent.
- the reduction reaction is performed in the same manner as in the synthesis of the compound (7).
- thionyl chloride and alcohol (13) are used in a solvent such as chlorophonolem, dichloromethane, ethinole acetate, ethenole, THF, or dioxane.
- methanesulfonylation methanesulfonyl chloride is used.
- the stirring is carried out at 0 ° C for 1 hour to several days, preferably for 5 hours.
- R 9 are the same as above.] That is, the compound (11) and the diamine derivative (9) are condensed to obtain a mono-substituted product (14), which is then reacted with the compound (8) to obtain a compound (la). In this reaction, the condensation reaction between the compound (11) and the diamine derivative (9) and the condensation reaction between the compound (14) and the compound (8) are respectively performed by the compound (10) and the compound (11). And the reaction of compound (8) with compound (9).
- R 11 represents a halogen atom or a hydroxy group
- R 1 R 2 , A 2 and Z are the same as above.
- the compound (1b) is obtained by condensing the compound (10), which is an acid chloride or a carboxylic acid, with the compound (10).
- the reaction between the acid chloride (15) and the compound (10) is carried out in a solvent such as chloroform and dichloromethane at 0 ° C. to a reflux temperature, preferably at room temperature for 1 hour to several days, preferably It is performed by stirring at B temple.
- Carboxylic acid (15) and compound (10) For example, in a solvent such as chloroform and dichloromethane, dicyclohexyl carpoimidide, 1-ethyl-3- (3-dimethylaminopropyl) carbopimid 'hydrochloride (water-soluble carbodiimide hydrochloride)
- a dehydrating condensing agent such as diisopropylpropylcarbodiimide at 0 ° C. to a reflux temperature, preferably at room temperature, for 10 minutes to several days, preferably for 6 hours.
- a 2 is CH 2 , CH 2 CH 2 or CH (CH 3 ), and R 1 and R 2 are the same as above. ]
- the compound (8) and the diamine derivative (9) are mixed with a solvent such as dimethylformamide (DMF), dimethylsulfoxide (DMSO), or acetonitrile in the presence of potassium carbonate from room temperature to 100 ° C, preferably 80 ° C.
- a solvent such as dimethylformamide (DMF), dimethylsulfoxide (DMSO), or acetonitrile in the presence of potassium carbonate from room temperature to 100 ° C, preferably 80 ° C.
- the compound (lc) is obtained by stirring at ° C for 1 hour to several days, preferably for 5 hours.
- a 1 — Z is a 2- (3,4,5-trimethoxyphenyl) pyridylmethyl group and A 2 is CO.
- the glycine methyl ester (16) is reacted with 2-2-trobenzene motivationfonyl chloride by a known method to obtain a 2-nitrobenzenesulfonyl compound (17).
- the compound (17) is reacted with the compound (8) under the same conditions as described above to obtain the compound (18).
- the compound (18) is treated by a known method to obtain a compound (19).
- Compound (19) is reduced with lithium aluminum hydride in the same manner as described above to obtain alcohol (20).
- Compound (20) is dissolved in a solvent such as dichloromethane, acetonitrile, DMF, or the like, in the presence of a base such as imidazole, triethylamine, 4-methylmorpholine, 4- (dimethylamino) pyridine, and tert-butyldimethylchlorosilane (TBD MS-C 1). And a reflux temperature of 0 ° C., preferably 50 ° C., for 1 hour to several days, preferably overnight, to obtain a TBDMS compound (21).
- a solvent such as dichloromethane, acetonitrile, DMF, or the like
- a base such as imidazole, triethylamine, 4-methylmorpholine, 4- (dimethylamino) pyridine, and tert-butyldimethylchlorosilane (TBD MS-C 1).
- TBD MS-C tert-butyldimethylchlorosilane
- Compound (21) was treated with 9-fluorenylmethoxycarbonyl amino acid (Fmoc-amino acid) (22) and dicyclohexylcarposimidate in a solvent such as chloroform, dichloromethane, acetonitrile, THF, DMF, DMSO, etc.
- a solvent such as chloroform, dichloromethane, acetonitrile, THF, DMF, DMSO, etc.
- the compound (24) is reacted with the above-mentioned 2-nitrobenzenesulfonyl chloride under the same conditions as described above to obtain a 2-nitrobenzenesulfonyl compound (25).
- the compound (25) is treated by a known method to obtain an alcohol (26).
- Compound (26) is dissolved in a solvent such as THF or dioxane, and triphenylphosphine and dimethyl ether carboxylate (DEAD) are refluxed at 0 ° C, preferably at room temperature for 1 hour to several days, preferably overnight.
- the compound (27) is obtained by the reaction.
- Compound (27) is subjected to de-2-nitrobenzenesulfonylation by a known method to obtain compound (28).
- the compound (1d) is obtained by reacting the compound (28) with the above chlorinated compound (8) under the same conditions as described above.
- N-benzylglycineethyl ester (29) is reacted with Fmoc-amino acid (N- (9-fluorenylmethoxycarbonyl) amino acid) (30) by a known method to obtain a dipeptide derivative (31).
- Compound (31) undergoes de-Fmoc cyclization and cyclization simultaneously by a known method to obtain diketobiperazine derivative (32).
- the compound (32) is treated by a known reduction method using lithium aluminum hydride or the like to obtain a piperazine derivative (33).
- Compound (33) is subjected to debenzylation by known catalytic reduction using palladium monocarbon to obtain compound (34).
- the compound (34) is reacted with the above-mentioned chlormouth (8) under the same conditions as described above to obtain a compound (1e).
- the compound (1) can be obtained by the above-mentioned method, and can be further purified by a usual purification means such as a recrystallization method and column chromatography, if necessary. If necessary, the desired salt or solvate can be prepared by a conventional method.
- the present invention includes all stereoisomers.
- the compound (1) thus obtained, or a salt or solvate thereof, exhibits an excellent inhibitory action on cancer cell growth as described in Examples below, and is useful as a therapeutic agent for cancer of human-containing animals.
- the cancer therapeutic agent of the present invention comprises the compound (1)., A salt thereof or a solvate thereof as an active ingredient.
- the administration form is not particularly limited and can be appropriately selected depending on the purpose of treatment. , Oral, injection, suppository, ointment, inhalant, eye drop, nasal drop, patch, and the like. Can be produced by a known and commonly used formulation method.
- an excipient and, if necessary, a binder, a disintegrant, a lubricant, a coloring agent, a flavoring agent, a flavoring agent, etc. are added to the compound (1), and then a conventional method is used.
- a conventional method is used.
- Such additives may be those commonly used in the art, such as lactose, sucrose, sodium chloride, glucose, starch, calcium carbonate, kaolin, microcrystals. Cellulose, silicic acid, etc.
- binders water, ethanol, propanol, simple syrup, dextrose solution, starch solution, gelatin solution, carboxy methinoresenolerose, hydroxypropinoresenorelose, hydroxypropinoresoreryl, methinoreser Oral, ethylethylenolose, shellac, canolesum phosphate, polyvinylpyrrolidone, etc.Disintegrants include dried starch, sodium alginate, agar powder, sodium hydrogen carbonate, calcium carbonate, sodium laurinole sulfate, monoglyceride stearate, milk Etc., as lubricants purified talc, stearic emissions salt, borax, polyethylene glycol, sucrose as a flavoring agent, orange peel, click Examples thereof include citric acid and tartaric acid.
- a flavoring agent When preparing an oral liquid preparation, add a flavoring agent, a buffer, a stabilizing agent, a flavoring agent, etc. to the compound (1) to produce an oral solution, a syrup, an elixir, etc. in a conventional manner.
- vanillin and the like are used as a flavoring agent
- sodium citrate and the like are used as a buffer
- tragacanth, acacia, gelatin and the like are used as a stabilizer.
- a pH adjuster, a buffer, a stabilizer, an isotonic agent, a local anesthetic, etc. are added to the compound (1), and a subcutaneous, intramuscular or intravenous injection is prepared by a conventional method.
- a pH adjusting agent and the buffer include sodium citrate, sodium acetate, sodium phosphate and the like.
- the stabilizer include sodium bisulfite, EDTA, thioglycolic acid, and thiolactic acid.
- Local anesthetics include proforce hydrochloride, lidocaine hydrochloride and the like.
- the isotonic agent include sodium chloride, glucose and the like.
- the compound (1) may be added to a pharmaceutical carrier known in the art, for example, polyethylene glycol, lanolin, cocoa butter, fatty acid triglyceride, and, if necessary, Tween (registered trademark). After adding a suitable surfactant and the like, it can be produced by an ordinary method.
- a pharmaceutical carrier known in the art, for example, polyethylene glycol, lanolin, cocoa butter, fatty acid triglyceride, and, if necessary, Tween (registered trademark).
- a base, a stabilizer, a wetting agent, a preservative, and the like which are usually used for the compound (1), are mixed as necessary, and mixed and formulated by a conventional method.
- the base include liquid paraffin, white petrolatum, beeswax, octyldodecyl alcohol, paraffin and the like.
- the preservative include methyl p-hydroxybenzoate, ethyl p-hydroxybenzoate, p-hydroxybenzoate and the like.
- inhalants In addition to the above, inhalants, eye drops, and nasal drops can be prepared by conventional methods.
- the cancer therapeutic agent of the present invention which can be obtained by intensively treating various cancers, for example, pituitary adenoma, auditory schwannoma, glioma, brain tumor, etc., brain, nerve, eye cancer, oral cancer (tongue cancer, oral floor cancer , Gum Cancer, ⁇ mucosal cancer, hard palate cancer), pharyngeal cancer (nasopharyngeal cancer, oropharyngeal cancer, hypopharyngeal cancer), laryngeal cancer (glottic, supraglottic, subglottic), maxillary, thyroid (papillary) , Follicular carcinoma, medullary carcinoma, undifferentiated carcinoma, malignant lymphoma), head and neck cancer such as salivary gland carcinoma (parotid carcinoma, submandibular carcinoma, sublingual carcinoma), thymoma, breast cancer, lung cancer, medium Liver-gallbladder and knee cancer, such as breast cancer such as dermatomas, gastric cancer,
- Urinary cancer such as penile cancer, testicular tumor, renal pelvis and ureteral cancer, prostate cancer, renal cell cancer, bladder cancer, vulvar cancer, uterine cancer, cervix cancer, endometrial cancer (endometrial cancer), uterus Gynecological cancers, such as sarcomas, villous diseases, vaginal cancer, breast cancer, ovarian cancer, ovarian germ cell tumors, malignant melanoma (melanoma), mycosis fungoides, skin cancer, etc.
- sarcomas such as penile cancer, testicular tumor, renal pelvis and ureteral cancer, prostate cancer, renal cell cancer, bladder cancer, vulvar cancer, uterine cancer, cervix cancer, endometrial cancer (endometrial cancer), uterus Gynecological cancers, such as sarcomas, villous diseases, vaginal cancer, breast cancer, ovarian cancer, ovarian germ cell tumors, malignant melanom
- malignant bone tumor osteosarcoma, paraosseous osteosarcoma, periosteal osteosarcoma, malignant fibrous histiocytoma, chordoma, Ewing sarcoma, adamancinoma, chondrosarcoma
- malignant soft tissue tumor malignant fibrous histiocytoma
- Liposarcoma synovial sarcoma, leiomyosarcoma, rhabdomyosarcoma, angiosarcoma, vascular sarcoma, lymphatic sarcoma, neurosarcoma, malignant neuroepitheloma, soft tissue Ewing sarcoma, extraosseous chondrosarcoma, extraosseous Bone and muscle cancers such as osteosarcoma, alveolar soft tissue sarcoma, epithelioid sarcoma, and clear cell sarcoma), malignant lymphoma, malignant lymphoma (n
- endocrine carcinomas such as cell tumors, knee endocrine tumors, parathyroid cancer and adrenal carcinoma
- pediatric cancers such as soft tissue sarcomas, brain tumors, retinoblastoma, Wilms tumors, and other cancers of unknown primary origin.
- the dose of the cancer therapeutic agent of the present invention varies depending on the age, body weight, symptoms, administration form, number of administrations, and the like. Usually, 1 to 100 mg of the compound (1) per day is 1 to adults. It is preferable to administer orally or parenterally once or several times.
- Example 1 1-[[2— (3,4,5-trimethoxyphenyl) pyridine-14-yl] methyl] pidazine (172 mg) and 4-bromolipenyl benzene (97 mg) The title compound was obtained by reacting in the same manner as described above to obtain a maleate salt. Yield: 60 mg (17%)
- Phenylboronic acid (147 mg) and ethyl 2-ethyl nicotinate (200 mg) were treated in the same manner as in Production Example 1 to obtain the title compound.
- Lithium aluminum hydride (579 mg) was added to anhydrous THF (4 OmL) under an argon stream and ice-cooling, and then 5,6,7-trimethoxynaphthalene-1-carboxylic acid (4.0 g) was added.
- An anhydrous THF solution (4 OmL) was added dropwise, and the mixture was stirred at room temperature for 4 hours.
- Ether (15 OmL) was added to the reaction solution, sodium sulfate decahydrate was added, and the mixture was stirred for 15 minutes.
- reaction solution was concentrated under reduced pressure, water was added to the residue, extracted with ethyl acetate, the organic layer was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
- Example 56 1-[[2- (3,4,5-trimethoxyphenol) pyridine-4-yl] methyl] pidazine (103 mg) and 3,4,5-trimethoxycholic acid (65 m g) was reacted as in Example 56 to give the title compound as the free base.
- Example 56 1-[[2- (3,4,5-trimethoxyphenyl) pyridine-14f1] methyl] piperazine (103 mg) and 2,3,4-trimethoxycholic acid (65 mg) were prepared in Example 56. The title compound was obtained as a free base.
- the anti-reaction solution is concentrated under reduced pressure and reduced pressure, and the residue residue is added with ethityl acetic acid acetic acid to the residue to obtain saturated sodium bicarbonate bicarbonate.
- the extract was washed, washed and washed with a saturated Japanese saline solution, dried and dried on anhydrous sodium sulfate sulfate, and concentrated under reduced pressure under reduced pressure. .
- reaction solution was concentrated under reduced pressure, ethyl acetate was added, washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
- reaction solution was concentrated under reduced pressure, ethyl acetate was added, and the mixture was washed with saturated aqueous sodium hydrogen carbonate, water, and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
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Abstract
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU2003280558A AU2003280558A1 (en) | 2002-10-11 | 2003-10-10 | Method for treatment of cancer |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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US41759802P | 2002-10-11 | 2002-10-11 | |
US60/417,598 | 2002-10-11 |
Publications (1)
Publication Number | Publication Date |
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WO2004032933A1 true WO2004032933A1 (fr) | 2004-04-22 |
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ID=32094044
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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PCT/JP2003/013048 WO2004032933A1 (fr) | 2002-10-11 | 2003-10-10 | Methode permettant de traiter le cancer |
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AU (1) | AU2003280558A1 (fr) |
WO (1) | WO2004032933A1 (fr) |
Cited By (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2008147864A2 (fr) * | 2007-05-22 | 2008-12-04 | Xenon Pharmaceuticals Inc. | Procédés d'utilisaton de composés pipérazine dans le traitement de maladies ou états médiés par le canal sodium |
US7767680B2 (en) | 2004-11-03 | 2010-08-03 | Vertex Pharmaceuticals Incorporated | Ion channel modulators and methods of use |
US8536186B2 (en) | 2008-08-04 | 2013-09-17 | Chdi Foundation, Inc. | Certain kynurenine-3-monooxygenase inhibitors, pharmaceutical compositions, and methods of use thereof |
RU2492163C9 (ru) * | 2009-04-03 | 2013-12-27 | Нэйчуруайз Байэутек & Медиклз Копэрейшн | Соединения коричной кислоты (варианты), промежуточные соединения для их получения, фармацевтическая композиция на их основе, способ ингибирования гистоновой деацетилазы, способ лечения диабета, способ лечения опухоли или заболевания, связанного с пролиферацией клеток, способ усиления роста аксонов и способ лечения нейродегенеративных заболеваний и спинной мышечной атрофии |
US8883785B2 (en) | 2010-01-25 | 2014-11-11 | Chdi Foundation, Inc. | Certain kynurenine-3-monooxygenase inhibitors, pharmaceutical compositions, and methods of use thereof |
US9428464B2 (en) | 2011-08-30 | 2016-08-30 | Chdi Foundation, Inc. | Kynurenine-3-monooxygenase inhibitors, pharmaceutical compositions, and methods of use thereof |
US9981918B2 (en) | 2011-08-30 | 2018-05-29 | Chdi Foundation, Inc. | Kynurenine-3-monooxygenase inhibitors, pharmaceutical compositions, and methods of use thereof |
US10258621B2 (en) | 2014-07-17 | 2019-04-16 | Chdi Foundation, Inc. | Methods and compositions for treating HIV-related disorders |
US10905687B2 (en) | 2016-10-27 | 2021-02-02 | Escalier Biosciences B.V. | Substituted piperazines as ROR-gamma modulators |
US11230555B2 (en) | 2018-03-12 | 2022-01-25 | Escalier Biosciences B.V. | Bicyclic RORγ modulators |
US11242350B2 (en) | 2018-03-12 | 2022-02-08 | Escalier Biosciences B.V. | Spirocyclic ROR-gamma modulators |
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WO1993022303A1 (fr) * | 1992-04-23 | 1993-11-11 | Glaxo Group Limited | Derives 1-piperazinacetiques utilises comme antagonistes de recepteur de fibrinogene |
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2003
- 2003-10-10 AU AU2003280558A patent/AU2003280558A1/en not_active Abandoned
- 2003-10-10 WO PCT/JP2003/013048 patent/WO2004032933A1/fr not_active Application Discontinuation
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WO1993022303A1 (fr) * | 1992-04-23 | 1993-11-11 | Glaxo Group Limited | Derives 1-piperazinacetiques utilises comme antagonistes de recepteur de fibrinogene |
EP0774257A2 (fr) * | 1995-11-20 | 1997-05-21 | Kowa Co. Ltd. | Dérivés de pipérazine et homopipérazine pour l'inhibition de l'adhésion et l'infiltration cellulaire |
US6432957B1 (en) * | 2001-06-29 | 2002-08-13 | Kowa Co., Ltd. | Piperazine derivative |
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Cited By (16)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8546414B2 (en) | 2004-11-03 | 2013-10-01 | Vertex Pharmaceuticals Incorporated | Ion channel modulators and methods of use |
US7767680B2 (en) | 2004-11-03 | 2010-08-03 | Vertex Pharmaceuticals Incorporated | Ion channel modulators and methods of use |
US8236815B2 (en) | 2004-11-03 | 2012-08-07 | Vertex Pharmaceuticals Incorporated | Ion channel modulators and methods of uses |
WO2008147864A3 (fr) * | 2007-05-22 | 2009-07-09 | Xenon Pharmaceuticals Inc | Procédés d'utilisaton de composés pipérazine dans le traitement de maladies ou états médiés par le canal sodium |
WO2008147864A2 (fr) * | 2007-05-22 | 2008-12-04 | Xenon Pharmaceuticals Inc. | Procédés d'utilisaton de composés pipérazine dans le traitement de maladies ou états médiés par le canal sodium |
US9145373B2 (en) | 2008-08-04 | 2015-09-29 | Chdi Foundation, Inc. | Certain kynurenine-3-monooxygenase inhibitors, pharmaceutical compositions, and methods of use thereof |
US8536186B2 (en) | 2008-08-04 | 2013-09-17 | Chdi Foundation, Inc. | Certain kynurenine-3-monooxygenase inhibitors, pharmaceutical compositions, and methods of use thereof |
RU2492163C9 (ru) * | 2009-04-03 | 2013-12-27 | Нэйчуруайз Байэутек & Медиклз Копэрейшн | Соединения коричной кислоты (варианты), промежуточные соединения для их получения, фармацевтическая композиция на их основе, способ ингибирования гистоновой деацетилазы, способ лечения диабета, способ лечения опухоли или заболевания, связанного с пролиферацией клеток, способ усиления роста аксонов и способ лечения нейродегенеративных заболеваний и спинной мышечной атрофии |
US8883785B2 (en) | 2010-01-25 | 2014-11-11 | Chdi Foundation, Inc. | Certain kynurenine-3-monooxygenase inhibitors, pharmaceutical compositions, and methods of use thereof |
US9428464B2 (en) | 2011-08-30 | 2016-08-30 | Chdi Foundation, Inc. | Kynurenine-3-monooxygenase inhibitors, pharmaceutical compositions, and methods of use thereof |
US9981918B2 (en) | 2011-08-30 | 2018-05-29 | Chdi Foundation, Inc. | Kynurenine-3-monooxygenase inhibitors, pharmaceutical compositions, and methods of use thereof |
US10258621B2 (en) | 2014-07-17 | 2019-04-16 | Chdi Foundation, Inc. | Methods and compositions for treating HIV-related disorders |
US10905687B2 (en) | 2016-10-27 | 2021-02-02 | Escalier Biosciences B.V. | Substituted piperazines as ROR-gamma modulators |
RU2753490C2 (ru) * | 2016-10-27 | 2021-08-17 | Эскальер Байосайенсес, Бв | Модуляторы ror-гамма |
US11230555B2 (en) | 2018-03-12 | 2022-01-25 | Escalier Biosciences B.V. | Bicyclic RORγ modulators |
US11242350B2 (en) | 2018-03-12 | 2022-02-08 | Escalier Biosciences B.V. | Spirocyclic ROR-gamma modulators |
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