JP3229693B2 - Piperazine derivative - Google Patents
Piperazine derivativeInfo
- Publication number
- JP3229693B2 JP3229693B2 JP03105593A JP3105593A JP3229693B2 JP 3229693 B2 JP3229693 B2 JP 3229693B2 JP 03105593 A JP03105593 A JP 03105593A JP 3105593 A JP3105593 A JP 3105593A JP 3229693 B2 JP3229693 B2 JP 3229693B2
- Authority
- JP
- Japan
- Prior art keywords
- compound
- carbamoyl
- amino
- dmso
- chloro
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- 150000004885 piperazines Chemical class 0.000 title claims description 5
- 150000001875 compounds Chemical class 0.000 claims description 60
- -1 carboxy, carbamoyl Chemical group 0.000 claims description 48
- 150000003839 salts Chemical class 0.000 claims description 18
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 7
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- 125000003545 alkoxy group Chemical group 0.000 claims description 5
- 125000004457 alkyl amino carbonyl group Chemical group 0.000 claims description 5
- 125000003282 alkyl amino group Chemical group 0.000 claims description 5
- 125000001589 carboacyl group Chemical group 0.000 claims description 5
- 229910052736 halogen Inorganic materials 0.000 claims description 5
- 150000002367 halogens Chemical class 0.000 claims description 5
- 125000000623 heterocyclic group Chemical group 0.000 claims description 4
- 150000002431 hydrogen Chemical class 0.000 claims description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- 229940103988 Adenosine uptake inhibitor Drugs 0.000 claims 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 33
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 30
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 27
- 239000000203 mixture Substances 0.000 description 23
- 239000000460 chlorine Substances 0.000 description 21
- 238000005160 1H NMR spectroscopy Methods 0.000 description 20
- 238000002844 melting Methods 0.000 description 20
- 230000008018 melting Effects 0.000 description 20
- 238000000034 method Methods 0.000 description 20
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 19
- 238000000921 elemental analysis Methods 0.000 description 19
- LLLHRNQLGUOJHP-UHFFFAOYSA-N 4-chloro-6,7-dimethoxyquinazoline Chemical compound C1=NC(Cl)=C2C=C(OC)C(OC)=CC2=N1 LLLHRNQLGUOJHP-UHFFFAOYSA-N 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- OIRDTQYFTABQOQ-KQYNXXCUSA-N adenosine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O OIRDTQYFTABQOQ-KQYNXXCUSA-N 0.000 description 10
- 238000001914 filtration Methods 0.000 description 9
- 230000002401 inhibitory effect Effects 0.000 description 9
- GVRRXASZZAKBMN-UHFFFAOYSA-N 4-chloroquinazoline Chemical compound C1=CC=C2C(Cl)=NC=NC2=C1 GVRRXASZZAKBMN-UHFFFAOYSA-N 0.000 description 8
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- 206010021143 Hypoxia Diseases 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- 239000002904 solvent Substances 0.000 description 8
- 238000004519 manufacturing process Methods 0.000 description 7
- 238000010992 reflux Methods 0.000 description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 239000002775 capsule Substances 0.000 description 6
- 229940126214 compound 3 Drugs 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
- 238000006243 chemical reaction Methods 0.000 description 5
- 238000009472 formulation Methods 0.000 description 5
- 238000002347 injection Methods 0.000 description 5
- 239000007924 injection Substances 0.000 description 5
- 206010002660 Anoxia Diseases 0.000 description 4
- 241000976983 Anoxia Species 0.000 description 4
- 239000002126 C01EB10 - Adenosine Substances 0.000 description 4
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-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
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 229960005305 adenosine Drugs 0.000 description 4
- 230000007953 anoxia Effects 0.000 description 4
- 239000000872 buffer Substances 0.000 description 4
- 238000007796 conventional method Methods 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- 238000001704 evaporation Methods 0.000 description 4
- 230000007954 hypoxia Effects 0.000 description 4
- 208000028867 ischemia Diseases 0.000 description 4
- 239000008101 lactose Substances 0.000 description 4
- 230000003680 myocardial damage Effects 0.000 description 4
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 description 4
- 239000002777 nucleoside Substances 0.000 description 4
- 150000003833 nucleoside derivatives Chemical class 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 238000010898 silica gel chromatography Methods 0.000 description 4
- 239000006188 syrup Substances 0.000 description 4
- 235000020357 syrup Nutrition 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- FDPHWQSGEWRZOL-UHFFFAOYSA-N 4,7-dichloroquinazoline Chemical compound ClC1=NC=NC2=CC(Cl)=CC=C21 FDPHWQSGEWRZOL-UHFFFAOYSA-N 0.000 description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 3
- FAAJBOIAPOXFAJ-UHFFFAOYSA-N C(N)(=O)C1N(CCN(C1)C1=NC=NC2=CC(=C(C=C12)OC)OC)CC(=O)NC1=C(C=C(C=C1Cl)[N+](=O)[O-])Cl Chemical compound C(N)(=O)C1N(CCN(C1)C1=NC=NC2=CC(=C(C=C12)OC)OC)CC(=O)NC1=C(C=C(C=C1Cl)[N+](=O)[O-])Cl FAAJBOIAPOXFAJ-UHFFFAOYSA-N 0.000 description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 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
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 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 3
- 229930006000 Sucrose Natural products 0.000 description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
- 229910052794 bromium Inorganic materials 0.000 description 3
- 230000005961 cardioprotection Effects 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- 210000003743 erythrocyte Anatomy 0.000 description 3
- 239000000796 flavoring agent Substances 0.000 description 3
- 235000019634 flavors Nutrition 0.000 description 3
- 239000008103 glucose Substances 0.000 description 3
- 125000005843 halogen group Chemical group 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 235000019359 magnesium stearate Nutrition 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 239000005720 sucrose Substances 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- WADSJYLPJPTMLN-UHFFFAOYSA-N 3-(cycloundecen-1-yl)-1,2-diazacycloundec-2-ene Chemical compound C1CCCCCCCCC=C1C1=NNCCCCCCCC1 WADSJYLPJPTMLN-UHFFFAOYSA-N 0.000 description 2
- 235000016623 Fragaria vesca Nutrition 0.000 description 2
- 240000009088 Fragaria x ananassa Species 0.000 description 2
- 235000011363 Fragaria x ananassa Nutrition 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
- 239000004372 Polyvinyl alcohol Substances 0.000 description 2
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 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 2
- 238000009835 boiling Methods 0.000 description 2
- SIHHLZPXQLFPMC-UHFFFAOYSA-N chloroform;methanol;hydrate Chemical compound O.OC.ClC(Cl)Cl SIHHLZPXQLFPMC-UHFFFAOYSA-N 0.000 description 2
- 229940125904 compound 1 Drugs 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 239000012442 inert solvent Substances 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- 239000006186 oral dosage form Substances 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 238000007911 parenteral administration Methods 0.000 description 2
- 239000002798 polar solvent Substances 0.000 description 2
- 229920002451 polyvinyl alcohol Polymers 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 239000008096 xylene Substances 0.000 description 2
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 1
- GLGNXYJARSMNGJ-VKTIVEEGSA-N (1s,2s,3r,4r)-3-[[5-chloro-2-[(1-ethyl-6-methoxy-2-oxo-4,5-dihydro-3h-1-benzazepin-7-yl)amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound CCN1C(=O)CCCC2=C(OC)C(NC=3N=C(C(=CN=3)Cl)N[C@H]3[C@H]([C@@]4([H])C[C@@]3(C=C4)[H])C(N)=O)=CC=C21 GLGNXYJARSMNGJ-VKTIVEEGSA-N 0.000 description 1
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 1
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 1
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 1
- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 description 1
- MWLJSFKNUGYJFI-UHFFFAOYSA-N 1-[2-(4-amino-2,6-dichloroanilino)-2-oxoethyl]piperazine-2-carboxamide Chemical compound NC(=O)C1CNCCN1CC(=O)NC1=C(Cl)C=C(N)C=C1Cl MWLJSFKNUGYJFI-UHFFFAOYSA-N 0.000 description 1
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 description 1
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 1
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 1
- DGHKCBSVAZXEPP-UHFFFAOYSA-N 2,4-dichloro-6,7-dimethoxyquinazoline Chemical compound ClC1=NC(Cl)=C2C=C(OC)C(OC)=CC2=N1 DGHKCBSVAZXEPP-UHFFFAOYSA-N 0.000 description 1
- TUQSVSYUEBNNKQ-UHFFFAOYSA-N 2,4-dichloroquinazoline Chemical compound C1=CC=CC2=NC(Cl)=NC(Cl)=C21 TUQSVSYUEBNNKQ-UHFFFAOYSA-N 0.000 description 1
- RVZMPNMUBCAPQO-UHFFFAOYSA-N 2,4-dimethoxyquinazoline Chemical compound C1=CC=CC2=NC(OC)=NC(OC)=C21 RVZMPNMUBCAPQO-UHFFFAOYSA-N 0.000 description 1
- VDYFFXPVIBDLOT-UHFFFAOYSA-N 2,4-dimethylquinazoline Chemical compound C1=CC=CC2=NC(C)=NC(C)=C21 VDYFFXPVIBDLOT-UHFFFAOYSA-N 0.000 description 1
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 1
- WMPTYRGXBUYONY-UHFFFAOYSA-N 2-chloroquinazoline Chemical compound C1=CC=CC2=NC(Cl)=NC=C21 WMPTYRGXBUYONY-UHFFFAOYSA-N 0.000 description 1
- BIICRHXSGPYQOV-UHFFFAOYSA-N 4-chloro-6,7,8-trimethoxyquinazoline Chemical compound N1=CN=C2C(OC)=C(OC)C(OC)=CC2=C1Cl BIICRHXSGPYQOV-UHFFFAOYSA-N 0.000 description 1
- QTAHKHWLAWFVQA-UHFFFAOYSA-N 4-chloro-6,8-dimethylquinazoline Chemical compound N1=CN=C(Cl)C2=CC(C)=CC(C)=C21 QTAHKHWLAWFVQA-UHFFFAOYSA-N 0.000 description 1
- 150000005168 4-hydroxybenzoic acids Chemical class 0.000 description 1
- FYMQPWWNOCENRN-UHFFFAOYSA-N 6,7-dimethoxyquinazoline Chemical compound N1=CN=C2C=C(OC)C(OC)=CC2=C1 FYMQPWWNOCENRN-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- SRBPALZYTGPABT-UHFFFAOYSA-N C(N)(=O)C1CN(CCN1C1=NC=NC2=CC=CC=C12)CC(=O)NC1=C(C=C(C=C1Cl)[N+](=O)[O-])Cl Chemical compound C(N)(=O)C1CN(CCN1C1=NC=NC2=CC=CC=C12)CC(=O)NC1=C(C=C(C=C1Cl)[N+](=O)[O-])Cl SRBPALZYTGPABT-UHFFFAOYSA-N 0.000 description 1
- DKDWRTHALMMLLW-UHFFFAOYSA-N C(N)(=O)C1N(CCN(C1)C1=NC=NC2=CC=CC=C12)CC(=O)NC1=C(C=C(C=C1Cl)[N+](=O)[O-])Cl Chemical compound C(N)(=O)C1N(CCN(C1)C1=NC=NC2=CC=CC=C12)CC(=O)NC1=C(C=C(C=C1Cl)[N+](=O)[O-])Cl DKDWRTHALMMLLW-UHFFFAOYSA-N 0.000 description 1
- RNELZCAMDDPLMF-UHFFFAOYSA-N C12=CC(C)=CC(C)=C2N=CN=C1N(C(C1)C(N)=O)CCN1CC(=O)NC1=C(Cl)C=C([N+]([O-])=O)C=C1Cl Chemical compound C12=CC(C)=CC(C)=C2N=CN=C1N(C(C1)C(N)=O)CCN1CC(=O)NC1=C(Cl)C=C([N+]([O-])=O)C=C1Cl RNELZCAMDDPLMF-UHFFFAOYSA-N 0.000 description 1
- 241000700198 Cavia Species 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 229940126657 Compound 17 Drugs 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 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
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical class CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 239000005715 Fructose Substances 0.000 description 1
- 229930091371 Fructose Natural products 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
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 244000246386 Mentha pulegium Species 0.000 description 1
- 235000016257 Mentha pulegium Nutrition 0.000 description 1
- 235000004357 Mentha x piperita Nutrition 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- LNUFLCYMSVYYNW-ZPJMAFJPSA-N [(2r,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[[(3s,5s,8r,9s,10s,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl]oxy]-4,5-disulfo Chemical compound O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)[C@H]1O[C@H](COS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@H](OS(O)(=O)=O)[C@H]1OS(O)(=O)=O LNUFLCYMSVYYNW-ZPJMAFJPSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 230000006229 amino acid addition Effects 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 230000003293 cardioprotective effect Effects 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 210000003710 cerebral cortex Anatomy 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 229940125773 compound 10 Drugs 0.000 description 1
- 229940125797 compound 12 Drugs 0.000 description 1
- 229940126543 compound 14 Drugs 0.000 description 1
- 229940125758 compound 15 Drugs 0.000 description 1
- 229940126142 compound 16 Drugs 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- NUVBSKCKDOMJSU-UHFFFAOYSA-N ethylparaben Chemical compound CCOC(=O)C1=CC=C(O)C=C1 NUVBSKCKDOMJSU-UHFFFAOYSA-N 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 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 description 1
- 235000001050 hortel pimenta Nutrition 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 1
- 239000000314 lubricant Substances 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
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 239000004014 plasticizer Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 235000019422 polyvinyl alcohol Nutrition 0.000 description 1
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 description 1
- 229910000105 potassium hydride Inorganic materials 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000004224 protection Effects 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- GPRLSGONYQIRFK-MNYXATJNSA-N triton Chemical compound [3H+] GPRLSGONYQIRFK-MNYXATJNSA-N 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Landscapes
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
【０００１】[0001]
【産業上の利用分野】本発明は、膜を通過するヌクレオ
シド輸送を阻害し細胞外のアデノシン濃度を増加させる
ことにより、虚血、無酸素症または低酸素症に起因する
心筋障害からの心臓保護に有用な、ピペラジン誘導体ま
たはその薬理的に許容される塩に関する。The present invention relates to cardioprotection from myocardial damage caused by ischemia, anoxia or hypoxia by inhibiting nucleoside transport across the membrane and increasing extracellular adenosine concentration. A piperazine derivative or a pharmaceutically acceptable salt thereof useful for
【０００２】[0002]
【従来の技術】アデノシン取り込み阻害作用を有する化
合物は、心筋保護作用を示すことが知られている［サー
キュレーション（Circul. ）、８０巻、１４００−１４
１１頁（１９８９年）；アメリカン ジャーナル オブ
フィジオロジー（Am. J. Physiol. ）、Ｈ１５７０−
１５７７頁（１９９１年）；ジャーナル オブ カルデ
ィオバスキュラー ファーマコロジー（J. Cardiovasc.
Pharmacol. ）、２０巻、１７３−１７８頁（１９９２
年）］。また、本発明に関連して、虚血、無酸素症また
は低酸素症に起因する心筋障害から心臓を保護する作用
を有する化合物として、ヌクレオシド輸送阻害剤である
Ｒ７５２３１（特開昭６３−２９０８６９号公報）が知
られている。2. Description of the Related Art Compounds having an adenosine uptake inhibitory activity are known to exhibit a cardioprotective activity [Circul., Vol. 80, 1400-14.
11 (1989); American Journal of Physiology (Am. J. Physiol.), H1570-
1577 (1991); Journal of Cardiovascular Pharmacology (J. Cardiovasc.
Pharmacol.), 20, 173-178 (1992).
Year)]. Further, in connection with the present invention, R75231, a nucleoside transport inhibitor (JP-A-63-290869), is a compound having an action of protecting the heart from myocardial damage caused by ischemia, anoxia or hypoxia. Gazette) is known.
【０００３】[0003]
【化２】 Embedded image
【０００４】[0004]
【発明が解決しようとする課題】本発明の目的は、ヌク
レオシド輸送阻害活性を有し、虚血、無酸素症または低
酸素症に起因する心筋障害からの心臓保護に有用な、新
規ピペラジン誘導体またはその薬理的に許容される塩を
提供することにある。SUMMARY OF THE INVENTION An object of the present invention is to provide a novel piperazine derivative having a nucleoside transport inhibitory activity, which is useful for cardioprotection from myocardial damage caused by ischemia, anoxia or hypoxia. It is to provide a pharmaceutically acceptable salt thereof.
【０００５】[0005]
【課題を解決するための手段】本発明は、式（Ｉ）According to the present invention, there is provided a compound of the formula (I)
【０００６】[0006]
【化３】 Embedded image
【０００７】（式中、Ｒ1、Ｒ2及びＲ3は同一または異
なって、水素、低級アルキル、低級アルコキシ、低級ア
ルカノイル、低級アルコキシカルボニル、カルボキシ、
カルバモイル、モノまたはジ低級アルキルアミノカルボ
ニル、トリフルオロメチル、ヒドロキシ、ハロゲン、ニ
トロ、アミノ、モノまたはジ低級アルキルアミノまたは
シアノを表し、Ｒ4は水素またはハロゲンを表し、Ｘは
水素、カルバモイル、モノまたはジ低級アルキルアミノ
カルボニル、低級アルコキシカルボニルまたはカルボキ
シを表し、ｎは１〜３の整数を表し、Ａｒは置換もしく
は非置換のアリールまたは置換もしくは非置換の複素環
基を表す）で表されるピペラジン誘導体またはその薬理
的に許容される塩に関する。(Wherein R 1 , R 2 and R 3 are the same or different and each represents hydrogen, lower alkyl, lower alkoxy, lower alkanoyl, lower alkoxycarbonyl, carboxy,
Carbamoyl, mono- or di-lower alkylaminocarbonyl, trifluoromethyl, hydroxy, halogen, nitro, amino, mono- or di-lower alkylamino or cyano, R 4 represents hydrogen or halogen, X is hydrogen, carbamoyl, mono or Di-lower alkylaminocarbonyl, lower alkoxycarbonyl or carboxy
And n represents an integer of 1 to 3, and Ar represents a substituted or unsubstituted aryl or a substituted or unsubstituted heterocyclic group) or a pharmaceutically acceptable salt thereof. .
【０００８】以下、式（Ｉ）で表される化合物を化合物
（Ｉ）という。他の式番号の化合物についても同様であ
る。式（Ｉ）の各基の定義において、低級アルキルおよ
び低級アルコキシ、低級アルカノイル、低級アルコキシ
カルボニル、モノまたはジ低級アルキルアミノカルボニ
ル、モノまたはジ低級アルキルアミノの低級アルキル部
分としては、直鎖または分枝状の炭素数１〜６の、例え
ば、メチル、エチル、プロピル、イソプロピル、ブチ
ル、イソブチル、sec-ブチル、tert- ブチル、ペンチ
ル、イソペンチル、ネオペンチル、ヘキシル等があげら
れ、ハロゲンは、フッ素、塩素、臭素、ヨウ素の各原子
を意味する。アリールとしては、例えば、フェニル、ナ
フチル等があげられ、複素環基としては、ピリジル、ピ
ラゾリル、キノリル、キナゾリル等があげられる。Hereinafter, the compound represented by the formula (I) is referred to as compound (I). The same applies to compounds of other formula numbers. In the definition of each group of the formula (I), the lower alkyl moiety of lower alkyl and lower alkoxy, lower alkanoyl, lower alkoxycarbonyl, mono- or di-lower alkylaminocarbonyl, mono- or di-lower alkylamino may be straight-chain or branched. C1-C6, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, etc., and halogen is fluorine, chlorine, It means each atom of bromine and iodine. Examples of the aryl include phenyl and naphthyl, and examples of the heterocyclic group include pyridyl, pyrazolyl, quinolyl, and quinazolyl.
【０００９】置換アリール及び置換複素環基の置換基と
しては、同一または異なって、置換数１〜３のハロゲ
ン、ニトロ、アミノ、シアノ、ヒドロキシ、トリフルオ
ロメチル、低級アルキル、低級アルコキシ、低級アルカ
ノイル、低級アルコキシカルボニル、モノまたはジ低級
アルキルアミノ等があげられる。置換基の定義におい
て、低級アルキル、低級アルコキシ、低級アルカノイ
ル、低級アルコキシカルボニル及びモノまたはジ低級ア
ルキルアミノは、前記と同意義を表す。The substituents of the substituted aryl and the substituted heterocyclic groups may be the same or different, and may have 1 to 3 halogen atoms, nitro, amino, cyano, hydroxy, trifluoromethyl, lower alkyl, lower alkoxy, lower alkanoyl, Lower alkoxycarbonyl, mono- or di-lower alkylamino and the like. In the definition of the substituent, lower alkyl, lower alkoxy, lower alkanoyl, lower alkoxycarbonyl and mono- or di-lower alkylamino have the same meanings as described above.
【００１０】化合物（Ｉ）の薬理的に許容される塩とし
ては、塩酸塩、硫酸塩、リン酸塩等の無機酸塩、酢酸
塩、マレイン酸塩、フマル酸塩、酒石酸塩、クエン酸塩
等の有機酸塩、リジン、グリシン、フェニルアラニン等
のアミノ酸付加塩があげられる。次に、化合物（Ｉ）の
製造法について説明する。The pharmaceutically acceptable salts of compound (I) include inorganic salts such as hydrochloride, sulfate and phosphate, acetate, maleate, fumarate, tartrate and citrate. And amino acid addition salts such as lysine, glycine and phenylalanine. Next, a method for producing the compound (I) will be described.
【００１１】なお、以下に示した製造方法において、定
義した基が実施方法の条件下変化するか、または方法を
実施するのに不適切な場合、有機合成化学で常用される
方法、例えば、官能基の保護、脱保護等の手段に付すこ
とにより、容易に実施することができる。 製造法１：化合物（Ｉ）は、次の反応工程に従い製造す
ることができる。In the production methods described below, if the defined groups change under the conditions of the practice method or are unsuitable for carrying out the method, a method commonly used in organic synthetic chemistry, for example, It can be easily carried out by applying means such as protection and deprotection of the group. Production method 1: Compound (I) can be produced according to the following reaction steps.
【００１２】[0012]
【化４】 Embedded image
【００１３】（式中、Ｌは塩素、臭素、ヨウ素等のハロ
ゲン原子、メタンスルホニルオキシ、トルエンスルホニ
ルオキシまたはベンゼンスルホニルオキシ等の脱離基を
表し、Ｒ1 、Ｒ2 、Ｒ3 、Ｒ4 、Ｘ、ｎ及びＡｒは前記
と同意義を表す）原料化合物（II）は、南アフリカ特許
６７ ０６５１２（１９６８）記載の方法に準じて得る
ことができる。また、原料化合物（III ）は、特開昭６
３−２９０８６９号公報記載の方法に準じて得ることが
できる。(Wherein L represents a halogen atom such as chlorine, bromine or iodine, or a leaving group such as methanesulfonyloxy, toluenesulfonyloxy or benzenesulfonyloxy, and R 1 , R 2 , R 3 , R 4 , X, n and Ar have the same meanings as above.) The starting compound (II) can be obtained according to the method described in South Africa Patent 670512 (1968). The starting compound (III) is disclosed in
It can be obtained according to the method described in JP-A-3-290869.
【００１４】化合物（Ｉ）は、化合物（II）と化合物
（III）とを、トリエチルアミン、ジイソプロピルエチ
ルアミン、ジアザビシクロウンデセン等の有機塩基、炭
酸カリウム、炭酸ナトリウム、水酸化ナトリウム、炭酸
水素ナトリウム等の金属塩等の塩基存在下、適当な不活
性溶媒、例えば、テトラヒドロフラン、ジオキサン等の
エーテル、メタノール、エタノール等のアルコール、ベ
ンゼン、トルエン、キシレン等の芳香族炭化水素、ジメ
チルスルホキシド、ジメチルホルムアミド、ニトロベン
ゼン等の非プロトン性極性溶媒、水等もしくはこれらの
混合溶媒中、０℃から用いた溶媒の沸点で、５分から２
４時間反応させることにより得ることができる。 製造法２： 化合物（Ｉ）は、次の反応工程に従い製造することもで
きる。Compound (I) is obtained by converting compound (II) and compound (III) into organic bases such as triethylamine, diisopropylethylamine, diazabicycloundecene, potassium carbonate, sodium carbonate, sodium hydroxide, sodium hydrogencarbonate and the like. In the presence of a base such as a metal salt of a suitable inert solvent, for example, tetrahydrofuran, dioxane
Alcohols such as ether , methanol, and ethanol; aromatic hydrocarbons such as benzene, toluene, and xylene; aprotic polar solvents such as dimethyl sulfoxide, dimethylformamide, and nitrobenzene; water, and the like; 5 to 2 minutes at the boiling point of the solvent
It can be obtained by reacting for 4 hours. Production Method 2: Compound (I) can also be produced according to the following reaction steps.
【００１５】[0015]
【化５】 Embedded image
【００１６】（式中、Ｐはエトキシカルボニル、アリル
オキシカルボニル、ベンジル等のアミノ基の保護基を表
し、Ｌ’は塩素、臭素、ヨウ素等のハロゲン原子、メタ
ンスルホニルオキシ、トルエンスルホニルオキシまたは
ベンゼンスルホニルオキシ等の脱離基を表し、Ｒ1、
Ｒ2、Ｒ3、Ｒ4、Ｘ、ｎ及びＡｒは前記と同意義を表
す）原料化合物（IV）は、ヨーロッパ特許公開０，０６
８，５４４号、米国特許３，２６７，１０４号または特
開昭６３−２９０８６９号公報記載の方法に準じて得る
ことができる。(Wherein, P represents an amino-protecting group such as ethoxycarbonyl, allyloxycarbonyl, benzyl, etc., L ′ represents a halogen atom such as chlorine, bromine, iodine, etc. Represents a leaving group such as oxy, and R 1 ,
R 2 , R 3 , R 4 , X, n and Ar have the same meanings as described above).
No. 8,544 , U.S. Pat. No. 3,267,104 or JP-A-63-290869.
【００１７】化合物（VI）は、化合物（III ）の代わり
に化合物（IV）を用い、製造法１の方法に準じて化合物
（Ｖ）を得た後、特開昭６３−２９０８６９号公報記載
の方法に準じて化合物（Ｖ）のアミノ基の保護基を脱保
護することにより得ることができる。次いで、化合物
（Ｉ）は、化合物（VI）と化合物（VII ）とを、トリエ
チルアミン、ジイソプロピルエチルアミン、ジアザビシ
クロウンデセン等の有機塩基、水素化ナトリウム、水素
化カリウム、ブチルリチウム、カリウムtert- ブトキシ
ド、炭酸カリウム、炭酸ナトリウム、水酸化ナトリウ
ム、炭酸水素ナトリウム等の金属塩等の塩基存在下、適
当な不活性溶媒、例えば、ジクロロメタン、クロロホム
等のハロゲン化炭化水素、テトラヒドロフラン、ジオキ
サン等のエーテル、メタノール、エタノール等のアルコ
ール、ベンゼン、トルエン、キシレン等の芳香族炭化水
素、ジメチルスルホキシド、ジメチルホルムアミド、ニ
トロベンゼン等の非プロトン性極性溶媒、水等もしくは
これらの混合溶媒中、０℃から用いた溶媒の沸点で、５
分から２４時間反応させることにより得ることができ
る。The compound (VI) is obtained by using the compound (IV) in place of the compound (III) to obtain a compound (V) according to the method of Production Method 1, and then obtaining the compound described in JP-A-63-290869. It can be obtained by deprotecting the amino-protecting group of compound (V) according to the method. Next, compound (I) is obtained by converting compound (VI) and compound (VII) into organic bases such as triethylamine, diisopropylethylamine, diazabicycloundecene, sodium hydride, potassium hydride, butyllithium, potassium tert-butoxide. In the presence of a base such as a metal salt such as potassium carbonate, sodium carbonate, sodium hydroxide, and sodium hydrogen carbonate, a suitable inert solvent, for example, a halogenated hydrocarbon such as dichloromethane or chlorohom, an ether such as tetrahydrofuran or dioxane, or methanol , Alcohols such as ethanol, aromatic hydrocarbons such as benzene, toluene and xylene, aprotic polar solvents such as dimethyl sulfoxide, dimethylformamide and nitrobenzene, water and the like, and the boiling point of the solvent used from 0 ° C. in a mixed solvent thereof And 5
It can be obtained by reacting for minutes to 24 hours.
【００１８】上記製造法における中間体および目的化合
物は、有機合成化学で常用される精製法、例えば、中
和、濾過、抽出、洗浄、乾燥、濃縮、再結晶、各種クロ
マトグラフィー等に付して単離精製することができる。
また、中間体においては、特に精製することなく次の反
応に供することも可能である。化合物（Ｉ）の塩を取得
したい時、化合物（Ｉ）が塩の形で得られる場合には、
そのまま精製すればよく、また、遊離の形で得られる場
合には、適当な有機溶媒に溶解もしくは懸濁させ、酸を
加える方法により塩を形成させればよい。The intermediates and the target compound in the above production method are subjected to purification methods commonly used in organic synthetic chemistry, for example, neutralization, filtration, extraction, washing, drying, concentration, recrystallization, various types of chromatography and the like. It can be isolated and purified.
In addition, the intermediate can be subjected to the next reaction without purification. When it is desired to obtain a salt of compound (I), when compound (I) is obtained in the form of a salt,
The salt may be purified as it is, or when it is obtained in a free form, dissolved or suspended in an appropriate organic solvent and a salt may be formed by adding an acid.
【００１９】また、化合物（Ｉ）及びその薬理的に許容
される塩は、水あるいは各種溶媒との付加物の形で存在
することもあるが、これら付加物も本発明に包含され
る。上記製造法によって得られる化合物（Ｉ）の具体例
を第１表に示す。The compound (I) and a pharmaceutically acceptable salt thereof may exist in the form of adducts with water or various solvents, and these adducts are also included in the present invention. Table 1 shows specific examples of the compound (I) obtained by the above production method.
【００２０】[0020]
【表１】 [Table 1]
【００２１】次に、代表的な化合物（Ｉ）の薬理作用に
ついて試験例で説明する。 試験例１．［3 Ｈ］−アデノシン取り込み阻害作用 健常成人男子（年齢４０歳未満）の上腕静脈よりクエン
酸−Ｎａ採血し、遠心分離操作により洗浄赤血球を得
た。赤血球懸濁液(2.5x109/ml)１００μｌに試験化合物
の２１％ジメチルスルホキシド（ＤＭＳＯ）溶液１０μ
ｌを添加後、１時間室温に放置し、［3 Ｈ］−アデノシ
ン溶液１０μｌを添加した。１０秒後、ジラゼップ溶液
(1mg/ml)２００μｌを添加して反応を停止した。Triton
X-100で赤血球を溶解した後、液体シンチレーションカ
ウンターで取り込まれた3 Ｈ量を測定した。［3 Ｈ］−
アデノシン取り込み阻害作用は、１０μＭでの阻害率に
より表した。結果を第２表に示した。Next, the pharmacological action of the representative compound (I) will be described with reference to test examples. Test Example 1 [ 3 H] -Adenosine uptake inhibitory action Blood was collected from the brachial vein of a healthy adult male (age less than 40 years) by citrate-Na, and washed erythrocytes were obtained by centrifugation. 100 μl of erythrocyte suspension (2.5 × 10 9 / ml) is added with 10 μl of a 21% dimethyl sulfoxide (DMSO) solution of the test compound.
After adding 1 l, the mixture was left at room temperature for 1 hour, and 10 μl of [ 3 H] -adenosine solution was added. 10 seconds later, dirazep solution
The reaction was stopped by adding 200 μl (1 mg / ml). Triton
After red blood cells were lysed with X-100, the amount of 3 H taken in by a liquid scintillation counter was measured. [ 3 H] −
The adenosine uptake inhibitory action was represented by the inhibition rate at 10 μM. The results are shown in Table 2.
【００２２】[0022]
【表２】 [Table 2]
【００２３】試験例２．［3 Ｈ］−ニトロベンジルチオ
イノシン（ＮＢＩ）結合阻害作用（アデノシン結合阻害
作用を見る１つの指標となる） ハートレー系雄性モルモットの大脳皮質に２５倍量（ｗ
／ｖ）の氷冷した５０mMトリス塩酸緩衝液ｐＨ７．４を
加えホモジナイズした。ホモジネートを遠心分離し（30
000xg, 4℃, 20分間）、上清を捨て、残りの沈澱に同量
の緩衝液を加えた。再びホモジナイズし、同様に遠心分
離した。残りの沈澱に２０倍量の緩衝液を加え懸濁し、
これを試験に用いた。Test Example 2. [ 3 H] -Nitrobenzylthioinosine (NBI) binding inhibitory activity (an indicator of adenosine binding inhibitory activity) A 25-fold amount (w) in the cerebral cortex of Hartley male guinea pigs
(V) ice-cold 50 mM Tris-HCl buffer pH 7.4 was added and homogenized. Centrifuge the homogenate (30
000 × g, 4 ° C., 20 minutes), the supernatant was discarded, and the same amount of buffer was added to the remaining precipitate. It was homogenized again and centrifuged similarly. The remaining precipitate was suspended by adding 20 volumes of buffer.
This was used for the test.
【００２４】試験化合物のＤＭＳＯ溶液に［3 Ｈ］−Ｎ
ＢＩ１．５nM及び組織ホモジネート５mg（湿重量）を加
え、混合物を２５℃で３０分間放置した。次いで、氷冷
した緩衝液４mlを加え、ガラスフィルター（ＧＦ／Ｃ
ワットマン社）あるいはレディーフィルター（ベックマ
ン社）上で急速吸引濾過することにより反応を停止し
た。フィルターをシンチレーションバイアルに移し、乾
燥後シンチゾルＥＸ−Ｈを加え、液体シンチレーション
カウンターで放射活性を測定した。［3 Ｈ］−ＮＢＩ結
合阻害作用は、１０μＭでの阻害率により表した。結果
を第３表に示した。[ 3 H] -N was added to a DMSO solution of the test compound.
1.5 nM BI and 5 mg (wet weight) tissue homogenate were added and the mixture was left at 25 ° C. for 30 minutes. Then, 4 ml of ice-cold buffer was added, and a glass filter (GF / C) was added.
The reaction was stopped by rapid suction filtration on Whatman) or a ready filter (Beckman). The filter was transferred to a scintillation vial. After drying, scintillator EX-H was added, and radioactivity was measured with a liquid scintillation counter. [ 3 H] -NBI binding inhibitory activity was represented by the inhibition rate at 10 μM. The results are shown in Table 3.
【００２５】[0025]
【表３】 [Table 3]
【００２６】化合物（Ｉ）またはその薬理的に許容され
る塩は、例えば錠剤、カプセル剤、シロップ剤等の通常
適用される剤形に調製して経口的に、あるいは、筋肉内
注射、静脈内注射、動脈内注射、点滴、坐剤等による直
腸内投与のような非経口的投与で投与することができ
る。それらの経口的または非経口的に投与する剤形の製
剤化には、通常知られた方法が適用され、例えば、経口
服用形態にある組成物の調製においては、何らかの有用
な薬理的に許容される担体が使用できる。例えば、懸濁
剤及びシロップ剤のような経口液体調製物は、水、例え
ばシュークロース、ソルビトール、フラクトース等の糖
類、例えばポリエチレングリコール、プロピレングリコ
ール等のグリコール類、例えばゴマ油、オリーブ類、大
豆油等の油類、例えばｐ−ヒドロキシ安息香酸エステル
類等の防腐剤、例えばストロベリーフレーバー、ペパー
ミント等のフレーバー類等を使用して製造できる。粉
剤、丸剤、カプセル剤及び錠剤は、例えばラクトース、
グルコース、シュークロース、マンニトール等の賦形
剤、例えばでん粉、アルギン酸ソーダ等の崩壊剤、例え
ばステアリン酸マグネシウム、タルク等の滑沢剤、例え
ばポリビニルアルコール、ヒドロキシプロピルセルロー
ス、ゼラチン等の結合剤、例えば脂肪酸エステル等の表
面活性剤、グリセリン等の可塑剤等を用いて製造でき
る。錠剤及びカプセル剤は、投与が容易であるという理
由で、最も有用な単位経口投与剤である。錠剤やカプセ
ル剤を製造する際には、固体の製薬担体が用いられる。The compound (I) or a pharmaceutically acceptable salt thereof is orally prepared, for example, in the form of tablets, capsules, syrups and the like, orally or intramuscularly or intravenously. Parenteral administration, such as injection, intraarterial injection, infusion, rectal administration with suppositories and the like, can be used. For the preparation of a dosage form for oral or parenteral administration, generally known methods are applied, for example, in the preparation of a composition in oral dosage form, any useful pharmacologically acceptable Carrier can be used. For example, oral liquid preparations such as suspensions and syrups can be prepared in water, for example, saccharides such as sucrose, sorbitol, and fructose; glycols such as polyethylene glycol and propylene glycol; For example, preservatives such as p-hydroxybenzoic acid esters, and flavors such as strawberry flavor and peppermint. Powders, pills, capsules and tablets include, for example, lactose,
Excipients such as glucose, sucrose, mannitol, and the like, disintegrants such as starch, sodium alginate, and the like, lubricants such as magnesium stearate, talc, and the like, binders such as polyvinyl alcohol, hydroxypropyl cellulose, gelatin, and the like, fatty acids It can be produced using a surfactant such as an ester and a plasticizer such as glycerin. Tablets and capsules are the most useful unit oral dosage forms because of their ease of administration. In producing tablets and capsules, solid pharmaceutical carriers are used.
【００２７】また、注射用の溶液は、蒸留水、塩溶液、
グルコース溶液または塩水とグルコース溶液の混合物か
ら成る担体を用いて調製することができる。化合物
（Ｉ）またはその薬理的に許容される塩の有効用量およ
び投与回数は、投与形態、患者の年齢、体重、症状等に
より異なるが、通常、１日当り、１〜1,000 mg／人を１
〜４回に分けて投与するのが好ましい。The solution for injection may be distilled water, salt solution,
It can be prepared using a carrier comprising a glucose solution or a mixture of saline and glucose solution. The effective dose and the number of administrations of the compound (I) or a pharmaceutically acceptable salt thereof vary depending on the administration form, patient age, body weight, symptoms and the like, but are usually 1 to 1,000 per day. mg / person 1
It is preferable to administer in 4 to 4 divided doses.
【００２８】[0028]
実施例１ Ｎ−（４−アミノ−２，６−ジクロロフェニル）−２−
カルバモイル−４−（６，７−ジメトキシ−４−キナゾ
リニル）−１−ピペラジンアセタミド （化合物１） ４−クロロ−６，７−ジメトキシキナゾリン（０．４５
ｇ）、Ｎ−（４−アミノ−２，６−ジクロロフェニル）
−２−カルバモイル−１−ピペラジンアセタミド（０．
６９ｇ）及びトリエチルアミン（０．２８ｍｌ）の混合
物を、メタノール（２０ｍｌ）中、還流条件下５時間撹
拌した。溶媒を減圧留去後、残渣をシリカゲルカラムク
ロマトグラフィーで精製し、標題の化合物（０．８５
ｇ，８０％）を得た。このうち０．４０ｇを、少量のク
ロロホルムを含むジエチルエーテルから結晶化した。こ
れを濾取、乾燥することにより、標題の化合物（０．３
３ｇ）を得た。Example 1 N- (4-amino-2,6-dichlorophenyl) -2-
Carbamoyl-4- (6,7-dimethoxy-4-quinazolinyl) -1-piperazineacetamide (Compound 1) 4-chloro-6,7-dimethoxyquinazoline (0.45
g), N- (4-amino-2,6-dichlorophenyl)
-2-carbamoyl-1-piperazine acetamide (0.
A mixture of 69 g) and triethylamine (0.28 ml) was stirred in methanol (20 ml) under reflux for 5 hours. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography to give the title compound (0.85
g, 80%). 0.40 g of this was crystallized from diethyl ether containing a small amount of chloroform. This was collected by filtration and dried to give the title compound (0.3
3 g) was obtained.
【００２９】融点：178.2-183.5 ℃ 元素分析：C23H25N7O4Cl2 ・2H2O 理論値(%) ; C 48.43, H 5.12, N 17.19 実測値(%) ; C 48.51, H 5.02, N 17.151 H-NMR(d6-DMSO) δ(ppm) : 9.58(s,1H), 8.59(s,1H),
7.94(s,1H), 7.58(s,1H), 7.50(s,1H), 7.24(s,1H), 6.
67(s,2H), 5.71(br s,2H), 3.97(s,3H), 3.94(s,3H),
3.0-4.1(m,8H), 2.77(m,1H). IR(KBr) : 1675, 1658, 1505, 1427, 1242, 1210, 113
3, 991.Melting point: 178.2-183.5 ° C. Elemental analysis: C 23 H 25 N 7 O 4 Cl 2 .2H 2 O Theoretical value (%); C 48.43, H 5.12, N 17.19 Actual value (%); C 48.51, H 5.02, N 17.15 1 H-NMR (d 6 -DMSO) δ (ppm): 9.58 (s, 1H), 8.59 (s, 1H),
7.94 (s, 1H), 7.58 (s, 1H), 7.50 (s, 1H), 7.24 (s, 1H), 6.
67 (s, 2H), 5.71 (br s, 2H), 3.97 (s, 3H), 3.94 (s, 3H),
3.0-4.1 (m, 8H), 2.77 (m, 1H) .IR (KBr): 1675, 1658, 1505, 1427, 1242, 1210, 113
3, 991.
【００３０】実施例２ Ｎ−（４−アミノ−２，６−ジクロロフェニル）−２−
カルバモイル−４−（４−キナゾリニル）−１−ピペラ
ジンアセタミド （化合物２） ４−クロロ−６，７−ジメトキシキナゾリンの代わりに
４−クロロキナゾリン（０．２４ｇ）を用いる以外は、
実施例１の方法に準じて、標題の化合物（０．３５ｇ，
６１％）を得た。Example 2 N- (4-amino-2,6-dichlorophenyl) -2-
Carbamoyl-4- (4-quinazolinyl) -1-piperazine acetamide (Compound 2) Except that 4-chloroquinazoline (0.24 g) is used instead of 4-chloro-6,7-dimethoxyquinazoline
According to the method of Example 1, the title compound (0.35 g,
61%).
【００３１】融点：186.3-187.0 ℃ 元素分析：C21H21N7O2Cl2 ・H2O 理論値(%) ; C 51.23, H 4.71, N 19.91 実測値(%) ; C 51.52, H 4.74, N 19.211 H-NMR(d6-DMSO) δ(ppm) : 9.57(s,1H), 8.65(s,1H),
8.15(d,1H,J=8.2Hz), 7.78-7.88(m,3H), 7.56(m,1H),
7.40(s,1H), 6.67(s,2H), 5.69(s,2H), 3.95-4.18(m,2
H), 3.64(m,1H), 3.05-3.45(m,5H), 2.68(m,1H). IR(KBr) : 1673, 1571, 1501, 1421, 799, 770.Melting point: 186.3-187.0 ° C. Elemental analysis: C 21 H 21 N 7 O 2 Cl 2 .H 2 O Theoretical value (%); C 51.23, H 4.71, N 19.91 Actual value (%); C 51.52, H 4.74, N 19.21 1 H-NMR (d 6 -DMSO) δ (ppm): 9.57 (s, 1H), 8.65 (s, 1H),
8.15 (d, 1H, J = 8.2Hz), 7.78-7.88 (m, 3H), 7.56 (m, 1H),
7.40 (s, 1H), 6.67 (s, 2H), 5.69 (s, 2H), 3.95-4.18 (m, 2
H), 3.64 (m, 1H), 3.05-3.45 (m, 5H), 2.68 (m, 1H) .IR (KBr): 1673, 1571, 1501, 1421, 799, 770.
【００３２】実施例３ Ｎ−（４−アミノ−２，６−ジクロロフェニル）−２−
カルバモイル−４−（６，７，８−トリメトキシ−４−
キナゾリニル）−１−ピペラジンアセタミド（化合物
３） ４−クロロ−６，７−ジメトキシキナゾリンの代わりに
４−クロロ−６，７，８−トリメトキシキナゾリン
（０．３５ｇ）を用いる以外は、実施例１の方法に準じ
て、標題の化合物（０．４９ｇ，７２％）を得た。Example 3 N- (4-amino-2,6-dichlorophenyl) -2-
Carbamoyl-4- (6,7,8-trimethoxy-4-
(Quinazolinyl) -1-piperazine acetamide (compound 3) Except for using 4-chloro-6,7,8-trimethoxyquinazoline (0.35 g) instead of 4-chloro-6,7-dimethoxyquinazoline. According to the method of Example 1, the title compound (0.49 g, 72%) was obtained.
【００３３】融点：150.1-150.9 ℃ 元素分析：C24H27N7O5Cl2 ・H2O 理論値(%) ; C 49.49, H 5.01, N 16.83 実測値(%) ; C 49.35, H 4.87, N 16.171 H-NMR(d6-DMSO) δ(ppm) : 9.57(s,1H), 8.61(s,1H),
7.91(s,1H), 7.48(s,1H), 7.39(s,1H), 6.67(s,2H), 5.
69(s,2H), 4.01(s,3H), 3.98(s,3H), 3.92(s,3H), 3.68
-3.88(m,3H), 3.15-3.55(m,5H), 2.75(m,1H). IR(KBr) : 1683, 1670, 1602, 1478, 1422, 1236, 112
6, 1022, 982, 803.Melting point: 150.1-150.9 ° C. Elemental analysis: C 24 H 27 N 7 O 5 Cl 2 .H 2 O Theoretical value (%); C 49.49, H 5.01, N 16.83 Actual value (%); C 49.35, H 4.87, N 16.17 1 H-NMR (d 6 -DMSO) δ (ppm): 9.57 (s, 1H), 8.61 (s, 1H),
7.91 (s, 1H), 7.48 (s, 1H), 7.39 (s, 1H), 6.67 (s, 2H), 5.
69 (s, 2H), 4.01 (s, 3H), 3.98 (s, 3H), 3.92 (s, 3H), 3.68
-3.88 (m, 3H), 3.15-3.55 (m, 5H), 2.75 (m, 1H) .IR (KBr): 1683, 1670, 1602, 1478, 1422, 1236, 112
6, 1022, 982, 803.
【００３４】実施例４ Ｎ−（４−アミノ−２，６−ジクロロフェニル）−２−
カルバモイル−４−（６，８−ジメチル−４−キナゾリ
ニル）−１−ピペラジンアセタミド （化合物４） ４−クロロ−６，７−ジメトキシキナゾリンの代わりに
４−クロロ−６，８−ジメチルキナゾリン（０．２８
ｇ）を用いる以外は、実施例１の方法に準じて、標題の
化合物（０．５２ｇ，７２％）を得た。Example 4 N- (4-amino-2,6-dichlorophenyl) -2-
Carbamoyl-4- (6,8-dimethyl-4-quinazolinyl) -1-piperazine acetamide (Compound 4) Instead of 4-chloro-6,7-dimethoxyquinazoline, 4-chloro-6,8-dimethylquinazoline ( 0.28
The title compound (0.52 g, 72%) was obtained according to the method of Example 1 except for using g).
【００３５】融点：169.3-171.6 ℃ 元素分析：C23H25N7O2Cl2 ・1.5H2O 理論値(%) ; C 52.18, H 5.33, N 18.52 実測値(%) ; C 52.13, H 4.95, N 17.981 H-NMR(d6-DMSO) δ(ppm) : 9.56(s,1H), 8.66(s,1H),
7.83(s,1H), 7.76(s,1H), 7.54(s,1H), 7.42(s,1H), 6.
67(s,2H), 5.70(s,2H), 3.85-4.06(m,2H), 3.69(m,1H),
3.56(m,1H), 3.17-3.44(m,3H), 3.11(m,1H), 2.68(m,1
H), 2.59(s,3H),2.46(s,3H). IR(KBr) : 3333, 1683, 1672, 1576, 1500, 1428, 133
6, 1244, 1131, 1076, 1014, 982, 955, 840, 801.Melting point: 169.3-171.6 ° C. Elemental analysis: C 23 H 25 N 7 O 2 Cl 2 .1.5H 2 O Theoretical value (%); C 52.18, H 5.33, N 18.52 Actual value (%); C 52.13, H 4.95, N 17.98 1 H-NMR (d 6 -DMSO) δ (ppm): 9.56 (s, 1H), 8.66 (s, 1H),
7.83 (s, 1H), 7.76 (s, 1H), 7.54 (s, 1H), 7.42 (s, 1H), 6.
67 (s, 2H), 5.70 (s, 2H), 3.85-4.06 (m, 2H), 3.69 (m, 1H),
3.56 (m, 1H), 3.17-3.44 (m, 3H), 3.11 (m, 1H), 2.68 (m, 1
H), 2.59 (s, 3H), 2.46 (s, 3H) .IR (KBr): 3333, 1683, 1672, 1576, 1500, 1428, 133
6, 1244, 1131, 1076, 1014, 982, 955, 840, 801.
【００３６】実施例５ Ｎ−（４−アミノ−２，６−ジクロロフェニル）−２−
カルバモイル−４−（７−クロロ−４−キナゾリニル）
−１−ピペラジンアセタミド （化合物５） ４−クロロ−６，７−ジメトキシキナゾリンの代わりに
４，７−ジクロロキナゾリン（０．４０ｇ）を用いる以
外は、実施例１の方法に準じて、標題の化合物（０．７
１ｇ，７０％）を得た。Example 5 N- (4-amino-2,6-dichlorophenyl) -2-
Carbamoyl-4- (7-chloro-4-quinazolinyl)
-1-Piperazine acetamide (Compound 5) The title was obtained according to the method of Example 1 except that 4,7-dichloroquinazoline (0.40 g) was used instead of 4-chloro-6,7-dimethoxyquinazoline. Compound (0.7
1 g, 70%).
【００３７】融点：184.6-185.2 ℃ 元素分析：C21H20N7O2Cl3 ・H2O 理論値(%) ; C 47.88, H 4.21, N 18.61 実測値(%) ; C 48.15, H 4.33, N 17.301 H-NMR(d6-DMSO) δ(ppm) : 9.56(s,1H), 8.64(s,1H),
8.20(d,1H,J=9.1Hz), 7.85(s,1H), 7.84(s,1H), 7.56
(d,1H,J=9.1Hz), 7.40(s,1H), 6.67(s,2H), 4.12(m,1
H), 4.01(m,1H), 3.81(m,1H), 3.71(m,1H), 3.20-3.45
(m,2H), 3.18(s,2H), 2.69(m,1H). IR(KBr) : 3300, 1680, 1598, 1560, 1504, 1440, 133
8, 1324, 1280, 1241, 1181, 1144, 1077, 1050, 958,
937, 883, 844, 803, 761, 661, 580.Melting point: 184.6-185.2 ° C. Elemental analysis: C 21 H 20 N 7 O 2 Cl 3 .H 2 O Theoretical value (%); C 47.88, H 4.21, N 18.61 Actual value (%); C 48.15, H 4.33, N 17.30 1 H-NMR (d 6 -DMSO) δ (ppm): 9.56 (s, 1H), 8.64 (s, 1H),
8.20 (d, 1H, J = 9.1Hz), 7.85 (s, 1H), 7.84 (s, 1H), 7.56
(d, 1H, J = 9.1Hz), 7.40 (s, 1H), 6.67 (s, 2H), 4.12 (m, 1
H), 4.01 (m, 1H), 3.81 (m, 1H), 3.71 (m, 1H), 3.20-3.45
(m, 2H), 3.18 (s, 2H), 2.69 (m, 1H) .IR (KBr): 3300, 1680, 1598, 1560, 1504, 1440, 133
8, 1324, 1280, 1241, 1181, 1144, 1077, 1050, 958,
937, 883, 844, 803, 761, 661, 580.
【００３８】実施例６ Ｎ−（４−アミノ−２，６−ジクロロフェニル）−２−
カルバモイル−４−（２−クロロ−６，７−ジメトキシ
−４−キナゾリニル）−１−ピペラジンアセタミド
（化合物６） ２，４−ジクロロ−６，７−ジメトキシキナゾリン
（０．５６ｇ）、Ｎ−（４−アミノ−２，６−ジクロロ
フェニル）−２−カルバモイル−１−ピペラジンアセタ
ミド（０．６９ｇ）及びトリエチルアミン（０．２８ｍ
ｌ）の混合物を、メタノール（２０ｍｌ）中、室温で４
０分間、さらに還流条件下３０分間撹拌した。析出した
結晶を濾取し、水及びメタノールで洗浄後、乾燥するこ
とにより、標題の化合物（０．９２ｇ，８１％）を得
た。Example 6 N- (4-amino-2,6-dichlorophenyl) -2-
Carbamoyl-4- (2-chloro-6,7-dimethoxy-4-quinazolinyl) -1-piperazineacetamide
(Compound 6) 2,4-dichloro-6,7-dimethoxyquinazoline (0.56 g), N- (4-amino-2,6-dichlorophenyl) -2-carbamoyl-1-piperazineacetamide (0.69 g) ) And triethylamine (0.28 m
l) in methanol (20 ml) at room temperature for 4 hours.
The mixture was stirred for 0 minute and further for 30 minutes under reflux condition. The precipitated crystals were collected by filtration, washed with water and methanol, and dried to give the title compound (0.92 g, 81%).
【００３９】融点：>300℃ 元素分析：C23H24N7O4Cl3 ・1.5H2O 理論値(%) ; C 46.36, H 4.56, N 16.45 実測値(%) ; C 46.95, H 4.24, N 16.141 H-NMR(d6-DMSO) δ(ppm) : 9.58(s,1H), 7.96(s,1H),
7.62(s,1H), 7.52(s,1H), 7.20(s,1H), 6.67(s,2H), 5.
70(s,2H), 3.97(s,3H), 3.93(s,3H), 3.0-4.2(m,8H),
2.82(m,1H). IR(KBr) : 1684, 1573, 1510, 1501, 1432, 1336, 124
5, 1220, 1148, 1135, 998, 962, 803.Melting point:> 300 ° C. Elemental analysis: C 23 H 24 N 7 O 4 Cl 3 .1.5H 2 O Theoretical value (%); C 46.36, H 4.56, N 16.45 Actual value (%); C 46.95, H 4.24, N 16.14 1 H-NMR (d 6 -DMSO) δ (ppm): 9.58 (s, 1H), 7.96 (s, 1H),
7.62 (s, 1H), 7.52 (s, 1H), 7.20 (s, 1H), 6.67 (s, 2H), 5.
70 (s, 2H), 3.97 (s, 3H), 3.93 (s, 3H), 3.0-4.2 (m, 8H),
2.82 (m, 1H). IR (KBr): 1684, 1573, 1510, 1501, 1432, 1336, 124
5, 1220, 1148, 1135, 998, 962, 803.
【００４０】実施例７ Ｎ−（４−アミノ−２，６−ジクロロフェニル）−３−
カルバモイル−４−（４−キナゾリニル）−１−ピペラ
ジンアセタミド （化合物７） ４−クロロキナゾリン（０．２０ｇ）、Ｎ−（４−アミ
ノ−２，６−ジクロロフェニル）−３−カルバモイル−
１−ピペラジンアセタミド（０．４２ｇ）及びトリエチ
ルアミン（０．１７ｍｌ）の混合物を、メタノール（１
５ｍｌ）中、還流条件下１時間撹拌した。溶媒を減圧留
去後、残渣をクロロホルム−メタノール−水で分配し、
有機層を減圧濃縮した。残渣をシリカゲルカラムクロマ
トグラフィーで精製し、ジエチルエーテルから結晶化し
た。これを濾取、乾燥することにより、標題の化合物
（０．１５ｇ，３９％）を得た。Example 7 N- (4-amino-2,6-dichlorophenyl) -3-
Carbamoyl-4- (4-quinazolinyl) -1-piperazine acetamide (Compound 7) 4-chloroquinazoline (0.20 g), N- (4-amino-2,6-dichlorophenyl) -3-carbamoyl-
A mixture of 1-piperazine acetamide (0.42 g) and triethylamine (0.17 ml) was added to methanol (1
5 ml) and stirred for 1 hour under reflux conditions. After evaporating the solvent under reduced pressure, the residue was partitioned with chloroform-methanol-water,
The organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and crystallized from diethyl ether. This was collected by filtration and dried to give the title compound (0.15 g, 39%).
【００４１】融点：186.7-187.1 ℃1 H-NMR(d6-DMSO) δ(ppm) : 9.34(s,1H), 8.63(s,1H),
8.22(s,1H), 8.09(d,1H,J=8.4Hz), 7.7-8.0(m,3H), 7.5
6(m,1H), 6.65(s,2H), 5.69(s,2H), 5.03(m,1H),4.21
(m,1H), 2.85-3.80(m,6H), 2.55(m,1H). IR(KBr) : 1679, 1566, 1496, 800, 767.Melting point: 186.7-187.1 ° C. 1 H-NMR (d 6 -DMSO) δ (ppm): 9.34 (s, 1H), 8.63 (s, 1H),
8.22 (s, 1H), 8.09 (d, 1H, J = 8.4Hz), 7.7-8.0 (m, 3H), 7.5
6 (m, 1H), 6.65 (s, 2H), 5.69 (s, 2H), 5.03 (m, 1H), 4.21
(m, 1H), 2.85-3.80 (m, 6H), 2.55 (m, 1H) .IR (KBr): 1679, 1566, 1496, 800, 767.
【００４２】実施例８ Ｎ−（４−アミノ−２，６−ジクロロフェニル）−３−
カルバモイル−４−（２−クロロ−６，７−ジメトキシ
−４−キナゾリニル）−１−ピペラジンアセタミド
（化合物８）４−クロロキナゾリン の代わりに２，４−ジクロロ−
６，７−ジメトキシキナゾリン（０．３５ｇ）を用いる
以外は、実施例７の方法に準じて、標題の化合物（０．
１１ｇ，１５％）を得た。Example 8 N- (4-amino-2,6-dichlorophenyl) -3-
Carbamoyl-4- (2-chloro-6,7-dimethoxy-4-quinazolinyl) -1-piperazineacetamide
(Compound 8) Instead of 4-chloroquinazoline , 2,4-dichloro-
Except that 6,7-dimethoxyquinazoline (0.35 g) was used, the title compound (0.
11 g, 15%).
【００４３】融点：>300℃ 元素分析：C23H24N7O4Cl3 ・H2O 理論値(%) ; C 47.07, H 4.47, N 16.71 実測値(%) ; C 47.21, H 4.08, N 15.991 H-NMR(d6-DMSO) δ(ppm) : 9.33(s,1H), 7.93(s,1H),
7.53(s,1H), 7.40(s,1H), 7.20(s,1H), 6.64(s,2H), 5.
69(s,2H), 4.94(m,1H), 4.21(m,1H), 3.93(s,3H), 3.89
(s,3H), 2.85-3.65(m,6H), 2.56(m,1H). IR(KBr) : 1685, 1625, 1600, 1573, 1510, 1475, 141
8, 1246, 1212, 1153, 1141, 997, 952, 805, 749.Melting point:> 300 ° C. Elemental analysis: C 23 H 24 N 7 O 4 Cl 3 .H 2 O Theoretical value (%); C 47.07, H 4.47, N 16.71 Actual value (%); C 47.21, H 4.08 , N 15.99 1 H-NMR (d 6 -DMSO) δ (ppm): 9.33 (s, 1H), 7.93 (s, 1H),
7.53 (s, 1H), 7.40 (s, 1H), 7.20 (s, 1H), 6.64 (s, 2H), 5.
69 (s, 2H), 4.94 (m, 1H), 4.21 (m, 1H), 3.93 (s, 3H), 3.89
(s, 3H), 2.85-3.65 (m, 6H), 2.56 (m, 1H). IR (KBr): 1685, 1625, 1600, 1573, 1510, 1475, 141
8, 1246, 1212, 1153, 1141, 997, 952, 805, 749.
【００４４】実施例９ ２−カルバモイル−Ｎ−（２，６−ジクロロ−４−ニト
ロフェニル）−４−（６，７−ジメトキシ−４−キナゾ
リニル）−１−ピペラジンアセタミド （化合物９） ４−クロロ−６，７−ジメトキシキナゾリン（０．３１
ｇ）、２−カルバモイル−Ｎ−（２，６−ジクロロ−４
−ニトロフェニル）−１−ピペラジンアセタミド（０．
４５ｇ）及びトリエチルアミン（０．１７ｍｌ）の混合
物を、メタノール（１５ｍｌ）中、還流条件下４時間４
０分撹拌した。溶媒を減圧留去後、残渣をクロロホルム
−メタノール−水で分配し、有機層を減圧濃縮した。残
渣をシリカゲルカラムクロマトグラフィーで精製し、ジ
エチルエーテルから結晶化した。これを濾取、乾燥する
ことにより、標題の化合物（０．４８ｇ，７１％）を得
た。Example 9 2-carbamoyl-N- (2,6-dichloro-4-nitrophenyl) -4- (6,7-dimethoxy-4-quinazolinyl) -1-piperazineacetamide (Compound 9) 4 -Chloro-6,7-dimethoxyquinazoline (0.31
g), 2-carbamoyl-N- (2,6-dichloro-4)
-Nitrophenyl) -1-piperazine acetamide (0.
45 g) and triethylamine (0.17 ml) in methanol (15 ml) under reflux for 4 hours.
Stirred for 0 minutes. After evaporating the solvent under reduced pressure, the residue was partitioned with chloroform-methanol-water, and the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and crystallized from diethyl ether. This was collected by filtration and dried to give the title compound (0.48 g, 71%).
【００４５】融点：247.2-247.4 ℃ 元素分析：C23H23N7O6Cl2 ・H2O 理論値(%) ; C 47.43, H 4.32, N 16.83 実測値(%) ; C 47.70, H 3.97, N 16.961 H-NMR(d6-DMSO) δ(ppm) : 10.26(s,1H), 8.59(s,1H),
8.44(s,2H), 7.91(s,1H), 7.57(s,1H), 7.54(s,1H),
3.97(s,3H), 3.94(s,3H), 3.2-4.0(m,8H), 2.84(m,1H). IR(KBr) : 1690, 1572, 1534, 1506, 1428, 1346, 124
3, 1214, 1137, 994, 808.Melting point: 247.2-247.4 ° C. Elemental analysis: C 23 H 23 N 7 O 6 Cl 2 .H 2 O Theoretical value (%); C 47.43, H 4.32, N 16.83 Actual value (%); C 47.70, H 3.97, N 16.96 1 H-NMR (d 6 -DMSO) δ (ppm): 10.26 (s, 1H), 8.59 (s, 1H),
8.44 (s, 2H), 7.91 (s, 1H), 7.57 (s, 1H), 7.54 (s, 1H),
3.97 (s, 3H), 3.94 (s, 3H), 3.2-4.0 (m, 8H), 2.84 (m, 1H) .IR (KBr): 1690, 1572, 1534, 1506, 1428, 1346, 124
3, 1214, 1137, 994, 808.
【００４６】実施例１０ ２−カルバモイル−Ｎ−（２，６−ジクロロ−４−ニト
ロフェニル）−４−（４−キナゾリニル）−１−ピペラ
ジンアセタミド （化合物１０） ４−クロロ−６，７−ジメトキシキナゾリンの代わりに
４−クロロキナゾリン（０．３０ｇ）を用いる以外は、
実施例９の方法に準じて、標題の化合物（０．６１ｇ，
５２％）を得た。Example 10 2-carbamoyl-N- (2,6-dichloro-4-nitrophenyl) -4- (4-quinazolinyl) -1-piperazineacetamide (compound 10) 4-chloro-6,7 -Except that 4-chloroquinazoline (0.30 g) is used instead of dimethoxyquinazoline
According to the method of Example 9, the title compound (0.61 g,
52%).
【００４７】融点：142.1-144.2 ℃ 元素分析：C21H19N7O4Cl2 ・H2O 理論値(%) ; C 48.29, H 4.05, N 18.77 実測値(%) ; C 48.40, H 3.96, N 19.051 H-NMR(d6-DMSO) δ(ppm) : 10.26(s,1H), 8.66(s,1H),
8.43(s,2H), 8.16(d,1H,J=8.4Hz), 7.65-8.00(m,3H),
7.57(m,1H), 7.43(s,1H), 3.85-4.25(m,2H), 3.0-3.9
(m,6H), 2.77(m,1H). IR(KBr) : 1698, 1675, 1575, 1536, 1500, 1345, 115
0, 1035, 947, 814, 775.Melting point: 142.1-144.2 ° C. Elemental analysis: C 21 H 19 N 7 O 4 Cl 2 .H 2 O Theoretical value (%); C 48.29, H 4.05, N 18.77 Actual value (%); C 48.40, H 3.96, N 19.05 1 H-NMR (d 6 -DMSO) δ (ppm): 10.26 (s, 1H), 8.66 (s, 1H),
8.43 (s, 2H), 8.16 (d, 1H, J = 8.4Hz), 7.65-8.00 (m, 3H),
7.57 (m, 1H), 7.43 (s, 1H), 3.85-4.25 (m, 2H), 3.0-3.9
(m, 6H), 2.77 (m, 1H) .IR (KBr): 1698, 1675, 1575, 1536, 1500, 1345, 115
0, 1035, 947, 814, 775.
【００４８】実施例１１ ２−カルバモイル−４−（７−クロロ−４−キナゾリニ
ル）−Ｎ−（２，６−ジクロロ−４−ニトロフェニル）
−１−ピペラジンアセタミド （化合物１１）４−クロ
ロ−６，７−ジメトキシキナゾリンの代わりに４，７−
ジクロロキナゾリン（０．４０ｇ）を用いる以外は、実
施例９の方法に準じて、標題の化合物（０．７８ｇ，７
２％）を得た。Example 11 2-carbamoyl- 4- (7-chloro-4-quinazolini
Ru) -N- (2,6-dichloro-4-nitrophenyl)
- 1-piperazine acetamide (compound 11) 4-chloro-6,7-dimethoxyquinazoline instead 4,7
The title compound (0.78 g, 7) was prepared according to the method of Example 9 except that dichloroquinazoline (0.40 g) was used.
2%).
【００４９】融点：159.5-161.4 ℃ 元素分析：C21H18N7O4Cl3 ・H2O 理論値(%) ; C 45.30, H 3.62, N 17.61 実測値(%) ; C 45.79, H 3.61, N 16.191 H-NMR(d6-DMSO) δ(ppm) : 10.25(s,1H), 8.65(s,1H),
8.42(s,2H), 8.20(d,1H,J=8.9Hz), 7.86(d,1H,J=2.0H
z), 7.81(s,1H), 7.56(dd,1H,J=8.9,2.0Hz), 7.42(s,1
H), 3.93-4.19(m,2H), 3.85(m,1H), 3.74(m,1H), 3.51
(m,1H), 3.22-3.42(m,1H), 3.18(s,2H), 3.16(s,2H),
2.77(m,1H). IR(KBr) : 3455, 3200, 1700, 1689, 1605, 1566, 153
1, 1485, 1438, 1390, 1347, 1273, 1187, 1151, 1090,
1037, 957, 886, 813, 784, 758, 744, 682.Melting point: 159.5-161.4 ° C. Elemental analysis: C 21 H 18 N 7 O 4 Cl 3 .H 2 O Theoretical value (%); C 45.30, H 3.62, N 17.61 Actual value (%); C 45.79, H 3.61, N 16.19 1 H-NMR (d 6 -DMSO) δ (ppm): 10.25 (s, 1H), 8.65 (s, 1H),
8.42 (s, 2H), 8.20 (d, 1H, J = 8.9Hz), 7.86 (d, 1H, J = 2.0H
z), 7.81 (s, 1H), 7.56 (dd, 1H, J = 8.9,2.0Hz), 7.42 (s, 1H
H), 3.93-4.19 (m, 2H), 3.85 (m, 1H), 3.74 (m, 1H), 3.51
(m, 1H), 3.22-3.42 (m, 1H), 3.18 (s, 2H), 3.16 (s, 2H),
2.77 (m, 1H) .IR (KBr): 3455, 3200, 1700, 1689, 1605, 1566, 153
1, 1485, 1438, 1390, 1347, 1273, 1187, 1151, 1090,
1037, 957, 886, 813, 784, 758, 744, 682.
【００５０】実施例１２ ３−カルバモイル−Ｎ−（２，６−ジクロロ−４−ニト
ロフェニル）−４−（４−キナゾリニル）−１−ピペラ
ジンアセタミド （化合物１２） ４−クロロキナゾリン（０．２５ｇ）、３−カルバモイ
ル−Ｎ−（２，６−ジクロロ−４−ニトロフェニル）−
１−ピペラジンアセタミド（０．５６ｇ）及びトリエチ
ルアミン（０．２１ｍｌ）の混合物を、水（８ｍｌ）及
びジオキサン（８ｍｌ）の混合溶媒中、室温で２５分
間、５０℃で３時間３５分、さらに還流条件下３時間２
５分撹拌した。室温まで冷却後、クロロホルムで抽出
し、有機層を無水硫酸マグネシウムで乾燥した。溶媒を
減圧留去後、残渣をシリカゲルカラムクロマトグラフィ
ーで精製し、クロロホルム／ジエチルエーテルから結晶
化した。これを濾取、乾燥することにより、標題の化合
物（０．２３ｇ，４２％）を得た。Example 12 3-carbamoyl-N- (2,6-dichloro-4-nitrophenyl) -4- (4-quinazolinyl) -1-piperazineacetamide (Compound 12) 4-chloroquinazoline (0.1%) 25 g), 3-carbamoyl-N- (2,6-dichloro-4-nitrophenyl)-
A mixture of 1-piperazine acetamide (0.56 g) and triethylamine (0.21 ml) was mixed in a mixed solvent of water (8 ml) and dioxane (8 ml) at room temperature for 25 minutes, at 50 ° C. for 3 hours and 35 minutes, and further. 3 hours under reflux condition 2
Stir for 5 minutes. After cooling to room temperature, the mixture was extracted with chloroform, and the organic layer was dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography and crystallized from chloroform / diethyl ether. This was collected by filtration and dried to give the title compound (0.23 g, 42%).
【００５１】融点：209.6-210.5 ℃ 元素分析：C21H19N7O4Cl2 理論値(%) ; C 50.01, H 3.80, N 19.44 実測値(%) ; C 50.26, H 3.71, N 19.061 H-NMR(d6-DMSO) δ(ppm) : 10.24(s,1H), 8.64(s,1H),
8.41(s,2H), 8.08(d,1H,J=9.4Hz), 8.70-8.95(m,3H),
7.57(m,1H), 7.49(m,1H), 5.05(m,1H), 4.22(m,1H), 3.
70(m,1H), 3.15-3.60(m,4H), 2.59(m,2H). IR(KBr) : 1700, 1680, 1610, 1563, 1532, 1490, 141
7, 1344, 1226, 1143, 1048, 999, 926, 814, 776.Melting point: 209.6-210.5 ° C. Elemental analysis: C 21 H 19 N 7 O 4 Cl 2 Theoretical value (%); C 50.01, H 3.80, N 19.44 Actual value (%); C 50.26, H 3.71, N 19.06 1 H-NMR (d 6 -DMSO) δ (ppm): 10.24 (s, 1H), 8.64 (s, 1H),
8.41 (s, 2H), 8.08 (d, 1H, J = 9.4Hz), 8.70-8.95 (m, 3H),
7.57 (m, 1H), 7.49 (m, 1H), 5.05 (m, 1H), 4.22 (m, 1H), 3.
70 (m, 1H), 3.15-3.60 (m, 4H), 2.59 (m, 2H) .IR (KBr): 1700, 1680, 1610, 1563, 1532, 1490, 141
7, 1344, 1226, 1143, 1048, 999, 926, 814, 776.
【００５２】実施例１３ ３−カルバモイル−４−（７−クロロ−４−キナゾリニ
ル）−Ｎ−（２，６−ジクロロ−４−ニトロフェニル）
−１−ピペラジンアセタミド （化合物１３）４−クロ
ロキナゾリンの代わりに４，７−ジクロロキナゾリン
（０．２６ｇ）を用いる以外は、実施例１２の方法に準
じて、標題の化合物（０．０６３ｇ，４％）を得た。Example 13 3-carbamoyl- 4- (7-chloro-4-quinazolini
Ru) -N- (2,6-dichloro-4-nitrophenyl)
- but using 1-piperazine acetamide (compound 13) 4-chloroquinazoline Instead 4,7 dichloroquinazoline of (0.26 g), according to the method of Example 12, the title compound (0.063 g , 4%).
【００５３】融点：215.7-217.5 ℃ 元素分析：C21H18N7O4Cl3 ・0.5H2O 理論値(%) ; C 46.05, H 3.50, N 17.90 実測値(%) ; C 46.15, H 3.22, N 17.601 H-NMR(d6-DMSO) δ(ppm) : 10.22(s,1H), 8.64(s,1H),
8.41(s,2H), 8.12(d,1H,J=7.1Hz), 7.87(s,1H), 7.81
(s,1H), 7.58(d,1H,J=7.1Hz), 7.49(s,1H), 5.10(m,1
H), 4.24(m,1H), 3.70(m,1H), 3.53(m,1H), 3.32(m,2
H), 2.97(m,1H), 2.59(m,2H). IR(KBr) : 3434, 3200, 1681, 1604, 1560, 1535, 148
4, 1423, 1388, 1345, 1312, 1178, 1144, 1103, 1072,
1046, 1002, 930, 882, 810, 741, 632.Melting point: 215.7-217.5 ° C. Elemental analysis: C 21 H 18 N 7 O 4 Cl 3 .0.5H 2 O Theoretical value (%); C 46.05, H 3.50, N 17.90 Actual value (%); C 46.15, H 3.22, N 17.60 1 H-NMR (d 6 -DMSO) δ (ppm): 10.22 (s, 1H), 8.64 (s, 1H),
8.41 (s, 2H), 8.12 (d, 1H, J = 7.1Hz), 7.87 (s, 1H), 7.81
(s, 1H), 7.58 (d, 1H, J = 7.1Hz), 7.49 (s, 1H), 5.10 (m, 1
H), 4.24 (m, 1H), 3.70 (m, 1H), 3.53 (m, 1H), 3.32 (m, 2
H), 2.97 (m, 1H), 2.59 (m, 2H) .IR (KBr): 3434, 3200, 1681, 1604, 1560, 1535, 148
4, 1423, 1388, 1345, 1312, 1178, 1144, 1103, 1072,
1046, 1002, 930, 882, 810, 741, 632.
【００５４】実施例１４ ３−カルバモイル−Ｎ−（２，６−ジクロロ−４−ニト
ロフェニル）−４−（６，８−ジメチル−４−キナゾリ
ニル）−１−ピペラジンアセタミド （化合物１４） ４−クロロキナゾリンの代わりに４−クロロ−６，８−
ジメチルキナゾリン（０．２６ｇ）を用いる以外は、実
施例１２の方法に準じて、標題の化合物（０．１３ｇ，
１８％）を得た。Example 14 3-carbamoyl-N- (2,6-dichloro-4-nitrophenyl) -4- (6,8-dimethyl-4-quinazolinyl) -1-piperazineacetamide (Compound 14) 4 -4-chloro-6,8- in place of chloroquinazoline
Except that dimethylquinazoline (0.26 g) was used, the title compound (0.13 g,
18%).
【００５５】融点：225.4-225.6 ℃ 元素分析：C23H23N7O4Cl2 ・0.5H2O 理論値(%) ; C 51.03, H 4.47, N 18.11 実測値(%) ; C 51.35, H 4.23, N 17.611 H-NMR(d6-DMSO) δ(ppm) : 10.24(s,1H), 8.65(s,1H),
8.41(s,2H), 7.75(s,1H), 7.68(s,1H), 7.55(s,1H),
7.44(s,1H), 4.95(m,1H), 4.08(m,1H), 3.69(m,1H), 3.
45(m,1H), 3.1-3.4(m,3H), 2.94(m,1H), 2.63(m,1H),
2.59(s,3H), 2.45(s,3H). IR(KBr) : 3432, 3200, 1699, 1680, 1573, 1533, 149
0, 1422, 1387, 1348, 1315, 1287, 1225, 1147, 1096,
1045, 996, 971, 947, 895, 882, 870, 814, 757,741.Melting point: 225.4-225.6 ° C. Elemental analysis: C 23 H 23 N 7 O 4 Cl 2 .0.5H 2 O Theoretical value (%); C 51.03, H 4.47, N 18.11 Actual value (%); C 51.35, H 4.23, N 17.61 1 H-NMR (d 6 -DMSO) δ (ppm): 10.24 (s, 1H), 8.65 (s, 1H),
8.41 (s, 2H), 7.75 (s, 1H), 7.68 (s, 1H), 7.55 (s, 1H),
7.44 (s, 1H), 4.95 (m, 1H), 4.08 (m, 1H), 3.69 (m, 1H), 3.
45 (m, 1H), 3.1-3.4 (m, 3H), 2.94 (m, 1H), 2.63 (m, 1H),
2.59 (s, 3H), 2.45 (s, 3H) .IR (KBr): 3432, 3200, 1699, 1680, 1573, 1533, 149
0, 1422, 1387, 1348, 1315, 1287, 1225, 1147, 1096,
1045, 996, 971, 947, 895, 882, 870, 814, 757, 741.
【００５６】実施例１５ Ｎ−（２，６−ジクロロ−４−ニトロフェニル）−４−
（６，７−ジメトキシ−４−キナゾリニル）−１−ピペ
ラジンアセタミド （化合物１５） ４−クロロ−６，７−ジメトキシキナゾリン（０．３４
ｇ）、Ｎ−（２，６−ジクロロ−４−ニトロフェニル）
−１−ピペラジンアセタミド（０．５０ｇ）及びトリエ
チルアミン（０．２１ｍｌ）の混合物を、メタノール
（２０ｍｌ）中、還流条件下１時間撹拌した。析出した
結晶を濾取し、水及びメタノールで洗浄後、乾燥するこ
とにより、標題の化合物（０．４７ｇ，７８％）を得
た。Example 15 N- (2,6-dichloro-4-nitrophenyl) -4-
(6,7-dimethoxy-4-quinazolinyl) -1-piperazine acetamide (Compound 15) 4-chloro-6,7-dimethoxyquinazoline (0.34
g), N- (2,6-dichloro-4-nitrophenyl)
A mixture of -1-piperazine acetamide (0.50 g) and triethylamine (0.21 ml) was stirred in methanol (20 ml) for 1 hour under reflux. The precipitated crystals were collected by filtration, washed with water and methanol, and dried to give the title compound (0.47 g, 78%).
【００５７】融点：205.7-206.1 ℃ 元素分析：C22H22N6O5Cl2 理論値(%) ; C 50.68, H 4.25, N 16.11 実測値(%) ; C 50.48, H 4.24, N 15.801 H-NMR(d6-DMSO) δ(ppm) : 10.10(br s,1H), 8.57(s,1
H), 8.41(s,2H), 7.23(s,1H), 7.14(s,1H), 3.94(s,3
H), 3.93(s,3H), 3.71(m,4H), 2.84(m,4H). IR(KBr) : 1723, 1619, 1577, 1532, 1503, 1474, 142
8, 1335, 1228, 1209, 1132, 996, 939, 847, 804, 79
2.Melting point: 205.7-206.1 ° C. Elemental analysis: C 22 H 22 N 6 O 5 Cl 2 Theoretical value (%); C 50.68, H 4.25, N 16.11 Actual value (%); C 50.48, H 4.24, N 15.80 1 H-NMR (d 6 -DMSO) δ (ppm): 10.10 (br s, 1H), 8.57 (s, 1
H), 8.41 (s, 2H), 7.23 (s, 1H), 7.14 (s, 1H), 3.94 (s, 3
H), 3.93 (s, 3H), 3.71 (m, 4H), 2.84 (m, 4H) .IR (KBr): 1723, 1619, 1577, 1532, 1503, 1474, 142
8, 1335, 1228, 1209, 1132, 996, 939, 847, 804, 79
2.
【００５８】実施例１６ Ｎ−（２，６−ジクロロ−４−ニトロフェニル）−４−
（４−キナゾリニル）−１−ピペラジンアセタミド
（化合物１６） ４−クロロ−６，７−ジメトキシキナゾリンの代わりに
４−クロロキナゾリン（０．２５ｇ）を用いる以外は、
実施例１５の方法に準じて、標題の化合物（０．６２
ｇ，６９％）を得た。Example 16 N- (2,6-dichloro-4-nitrophenyl) -4-
(4-quinazolinyl) -1-piperazine acetamide
(Compound 16) Except for using 4-chloroquinazoline (0.25 g) instead of 4-chloro-6,7-dimethoxyquinazoline,
According to the method of Example 15, the title compound (0.62
g, 69%).
【００５９】融点：175.4-176.5 ℃ 元素分析：C20H18N6O3Cl2 理論値(%) ; C 52.07, H 3.93, N 18.22 実測値(%) ; C 51.98, H 3.86, N 18.051 H-NMR(d6-DMSO) δ(ppm) : 9.27(s,1H), 8.79(s,1H),
8.29(s,2H), 7.94(d,1H,J=8.4Hz), 7.91(d,1H,J=8.9H
z), 7.78(m,1H), 7.51(m,1H), 3.87(m,4H), 3.38(s,2
H), 2.98(m,4H). IR(KBr) : 3300, 1703, 1614, 1570, 1532, 1503, 148
1, 1445, 1346, 1331, 1260, 1146, 1088, 1012, 941,
839, 808, 758, 687.Melting point: 175.4-176.5 ° C. Elemental analysis: C 20 H 18 N 6 O 3 Cl 2 Theoretical value (%); C 52.07, H 3.93, N 18.22 Actual value (%); C 51.98, H 3.86, N 18.05 1 H-NMR (d 6 -DMSO) δ (ppm): 9.27 (s, 1H), 8.79 (s, 1H),
8.29 (s, 2H), 7.94 (d, 1H, J = 8.4Hz), 7.91 (d, 1H, J = 8.9H
z), 7.78 (m, 1H), 7.51 (m, 1H), 3.87 (m, 4H), 3.38 (s, 2
H), 2.98 (m, 4H) .IR (KBr): 3300, 1703, 1614, 1570, 1532, 1503, 148
1, 1445, 1346, 1331, 1260, 1146, 1088, 1012, 941,
839, 808, 758, 687.
【００６０】実施例１７ Ｎ−（４−アミノ−２，６−ジクロロフェニル）−４−
（６，７−ジメトキシ−４−キナゾリニル）−１−ピペ
ラジンアセタミド （化合物１７） ４−クロロ−６，７−ジメトキシキナゾリン（０．３４
ｇ）、Ｎ−（４−アミノ−２，６−ジクロロフェニル）
−１−ピペラジンアセタミド（０．４６ｇ）及びトリエ
チルアミン（０．２１ｍｌ）の混合物を、メタノール
（２０ｍｌ）中、還流条件下１時間撹拌した。溶媒を減
圧留去し、析出した結晶を濾取した後、メタノールで洗
浄し、乾燥することにより、標題の化合物（０．３９
ｇ，５１％）を得た。Example 17 N- (4-amino-2,6-dichlorophenyl) -4-
(6,7-dimethoxy-4-quinazolinyl) -1-piperazine acetamide (Compound 17) 4-chloro-6,7-dimethoxyquinazoline (0.34
g), N- (4-amino-2,6-dichlorophenyl)
A mixture of -1-piperazine acetamide (0.46 g) and triethylamine (0.21 ml) was stirred in methanol (20 ml) for 1 hour under reflux. The solvent was distilled off under reduced pressure, and the precipitated crystals were collected by filtration, washed with methanol, and dried to give the title compound (0.39).
g, 51%).
【００６１】融点：174.5-176.5 ℃ 元素分析：C22H24N6O3Cl2 ・1.5H2O 理論値(%) ; C 50.97, H 5.25, N 16.21 実測値(%) ; C 51.01, H 5.17, N 15.991 H-NMR(d6-DMSO) δ(ppm) : 9.31(s,1H), 8.56(s,1H),
7.22(s,1H), 7.13(s,1H), 6.65(s,2H), 5.68(s,2H), 3.
93(s,3H), 3.92(s,3H), 3.69(m,4H), 2.79(m,4H). IR(KBr) : 1683, 1618, 1582, 1504, 1480, 1428, 133
5, 1241, 1212, 1136, 1000, 848, 797.Melting point: 174.5-176.5 ° C. Elemental analysis: C 22 H 24 N 6 O 3 Cl 2 .1.5H 2 O Theoretical value (%); C 50.97, H 5.25, N 16.21 Actual value (%); C 51.01, H 5.17, N 15.99 1 H-NMR (d 6 -DMSO) δ (ppm): 9.31 (s, 1H), 8.56 (s, 1H),
7.22 (s, 1H), 7.13 (s, 1H), 6.65 (s, 2H), 5.68 (s, 2H), 3.
93 (s, 3H), 3.92 (s, 3H), 3.69 (m, 4H), 2.79 (m, 4H) .IR (KBr): 1683, 1618, 1582, 1504, 1480, 1428, 133
5, 1241, 1212, 1136, 1000, 848, 797.
【００６２】実施例１８ Ｎ−（４−アミノ−２，６−ジクロロフェニル）−４−
（４−キナゾリニル）−１−ピペラジンアセタミド
（化合物１８） ４−クロロ−６，７−ジメトキシキナゾリンの代わりに
４−クロロキナゾリン（０．２７ｇ）を用いる以外は、
実施例１７の方法に準じて、標題の化合物（０．３７
ｇ，５２％）を得た。Example 18 N- (4-amino-2,6-dichlorophenyl) -4-
(4-quinazolinyl) -1-piperazine acetamide
(Compound 18) Except for using 4-chloroquinazoline (0.27 g) instead of 4-chloro-6,7-dimethoxyquinazoline,
According to the method of Example 17, the title compound (0.37
g, 52%).
【００６３】融点：208.5-209.4 ℃ 元素分析：C20H20N6OCl2・0.5H2O 理論値(%) ; C 54.55, H 4.81, N 19.09 実測値(%) ; C 54.99, H 4.61, N 19.141 H-NMR(d6-DMSO) δ(ppm) : 9.32(s,1H), 8.63(s,1H),
8.02(d,1H,J=8.4Hz), 7.74-7.90(s,2H), 7.55(m,1H),
6.65(s,2H), 5.67(s,2H), 3.82(m,4H), 3.19(s,2H), 2.
78(m,4H). IR(KBr) : 3200, 1670, 1612, 1568, 1506, 1434, 132
1, 1134, 1010, 941, 830,802, 770, 682.Melting point: 208.5-209.4 ° C. Elemental analysis: C 20 H 20 N 6 OCl 2 .0.5H 2 O Theoretical value (%); C 54.55, H 4.81, N 19.09 Actual value (%); C 54.99, H 4.61 , N 19.14 1 H-NMR (d 6 -DMSO) δ (ppm): 9.32 (s, 1H), 8.63 (s, 1H),
8.02 (d, 1H, J = 8.4Hz), 7.74-7.90 (s, 2H), 7.55 (m, 1H),
6.65 (s, 2H), 5.67 (s, 2H), 3.82 (m, 4H), 3.19 (s, 2H), 2.
78 (m, 4H) .IR (KBr): 3200, 1670, 1612, 1568, 1506, 1434, 132
1, 1134, 1010, 941, 830,802, 770, 682.
【００６４】実施例１９ Ｎ−（４−アミノ−２，６−ジクロロフェニル）−４−
（７−クロロ−４−キナゾリニル）−１−ピペラジンア
セタミド （化合物１９） ４−クロロ−６，７−ジメトキシキナゾリンの代わりに
４，７−ジクロロキナゾリン（０．３３ｇ）を用いる以
外は、実施例１７の方法に準じて、標題の化合物（０．
１５ｇ，１９％）を得た。Example 19 N- (4-amino-2,6-dichlorophenyl) -4-
(7-Chloro-4-quinazolinyl) -1-piperazine acetamide (Compound 19) Except that 4,7-dichloroquinazoline (0.33 g) was used instead of 4-chloro-6,7-dimethoxyquinazoline. According to the method of Example 17, the title compound (0.
15 g, 19%).
【００６５】融点：236.4-237.4 ℃ 元素分析：C20H19N6OCl3・H2O 理論値(%) ; C 49.65, H 4.38, N 17.37 実測値(%) ; C 50.32, H 4.55, N 16.311 H-NMR(d6-DMSO) δ(ppm) : 9.32(s,1H), 8.62(s,1H),
8.04(d,1H,J=8.9Hz), 7.84(d,1H,J=2.2Hz), 7.54(dd,1
H,J=8.9,2.2Hz), 6.65(s,2H), 5.67(s,2H), 3.86(m,4
H), 3.17(s,2H), 2.76(m,4H). IR(KBr) : 3435, 3225, 1680, 1607, 1564, 1540, 145
5, 1335, 1326, 1264, 1177, 1146, 1093, 1075, 1032,
1013, 948, 881, 794, 783.Melting point: 236.4-237.4 ° C. Elemental analysis: C 20 H 19 N 6 OCl 3 .H 2 O Theoretical value (%); C 49.65, H 4.38, N 17.37 Actual value (%); C 50.32, H 4.55, N 16.31 1 H-NMR (d 6 -DMSO) δ (ppm): 9.32 (s, 1H), 8.62 (s, 1H),
8.04 (d, 1H, J = 8.9Hz), 7.84 (d, 1H, J = 2.2Hz), 7.54 (dd, 1
H, J = 8.9,2.2Hz), 6.65 (s, 2H), 5.67 (s, 2H), 3.86 (m, 4
H), 3.17 (s, 2H), 2.76 (m, 4H) .IR (KBr): 3435, 3225, 1680, 1607, 1564, 1540, 145
5, 1335, 1326, 1264, 1177, 1146, 1093, 1075, 1032,
1013, 948, 881, 794, 783.
【００６６】実施例２０Ｎ− （４−アミノ−２，６−ジクロロフェニル）−２−
カルバモイル−４−（６，７−ジメトキシ−４−キナゾ
リニル）−１−ピペラジンアセタミド３塩酸塩（化合物
１の３塩酸塩） 実施例１で得られた化合物（０．４５ｇ）をクロロホル
ム及びメタノールの混合溶媒に溶解し、これに塩酸飽和
酢酸エチル溶液を加えた。この混合物を、ジエチルエー
テル中に加え、析出した結晶を濾取、乾燥し、標題の化
合物（０．４４ｇ，６５％）を得た。Example 20 N- (4-amino-2,6-dichlorophenyl) -2-
Carbamoyl- 4- (6,7-dimethoxy-4-quinazolinyl) -1-piperazine acetamide trihydrochloride (trihydrochloride of compound 1) The compound (0.45 g) obtained in Example 1 was subjected to chloroform and methanol. And a hydrochloric acid-saturated ethyl acetate solution was added thereto. This mixture was added to diethyl ether, and the precipitated crystals were collected by filtration and dried to give the title compound (0.44 g, 65%).
【００６７】融点：183.7-196.8 ℃ 元素分析：C23H25N7O4Cl2 ・3HCl・2.5H2O 理論値(%) ; C 40.10, H 4.82, N 14.23 実測値(%) ; C 40.29, H 5.01, N 14.351 H-NMR(d6-DMSO) δ(ppm) : 10.09(s,1H), 8.89(s,1H),
8.26(s,1H), 7.73(s,1H), 7.56(s,1H), 7.53(s,1H),
6.80(s,2H), 5.36(br s,2H), 4.00(s,3H), 3.99(s,3H),
3.20-4.75(m,9H). IR(KBr) : 1698, 1691, 1620, 1500, 1372, 1286, 121
8, 987, 799.Melting point: 183.7-196.8 ° C. Elemental analysis: C 23 H 25 N 7 O 4 Cl 2 .3HCl.2.5H 2 O Theoretical value (%); C 40.10, H 4.82, N 14.23 Actual value (%); C 40.29, H 5.01, N 14.35 1 H-NMR (d 6 -DMSO) δ (ppm): 10.09 (s, 1H), 8.89 (s, 1H),
8.26 (s, 1H), 7.73 (s, 1H), 7.56 (s, 1H), 7.53 (s, 1H),
6.80 (s, 2H), 5.36 (br s, 2H), 4.00 (s, 3H), 3.99 (s, 3H),
3.20-4.75 (m, 9H). IR (KBr): 1698, 1691, 1620, 1500, 1372, 1286, 121
8, 987, 799.
【００６８】製剤例１ 錠剤 常法により、次の組成からなる錠剤を作成する。 化合物３ ５０mg 乳 糖 １５０mg 馬鈴薯でんぷん ７５mg ポリビニルアルコール ７.5mg ステアリン酸マグネシウム ２.5mgFormulation Example 1 Tablet A tablet having the following composition is prepared by a conventional method. Compound 3 50mg Lactose 150mg Potato starch 75mg Polyvinyl alcohol 7.5mg Magnesium stearate 2.5mg
【００６９】製剤例２ 散剤 常法により、次の組成からなる散剤を作成する。 化合物３ ５０mg 乳 糖 ７５０mgFormulation Example 2 Powder A powder having the following composition is prepared by a conventional method. Compound 3 50mg Lactose 750mg
【００７０】製剤例３ カプセル剤 常法により、次の組成からなるカプセル剤を作成する。 化合物３ ５０mg 乳 糖 ５００mg ステアリン酸マグネシウム １２.5mg これを混合し、ゼラチンカプセルに充填する。Formulation Example 3 Capsules A capsule having the following composition is prepared by a conventional method. Compound 3 50 mg Lactose 500 mg Magnesium stearate 12.5 mg Mix this and fill into gelatin capsules.
【００７１】製剤例４ シロップ剤 常法により、次の組成からなるシロップ剤を作成する。 化合物３ ５０mg 精製白糖 ７５mg ｐ−ヒドロキシ安息香酸エチルエステル １００mg ｐ−ヒドロキシ安息香酸プロピルエステル ２５mg ストロベリーフレーバー ０．２５ml これに水を加えて全量１００mlとする。Formulation Example 4 Syrup A syrup having the following composition is prepared by a conventional method. Compound 3 50 mg Purified sucrose 75 mg p-hydroxybenzoic acid ethyl ester 100 mg p-hydroxybenzoic acid propyl ester 25 mg strawberry flavor 0.25 ml To this is added water to make a total volume of 100 ml.
【００７２】製剤例５ 注射剤 常法により、次の組成からなる注射剤を作成する。 化合物３ ２０mg 塩化ナトリウム ４５mg これに水を加えて全量５mlとする（１アンプル分）。な
お、水はあらかじめ蒸留し、オートクレーブ中滅菌して
ある。Formulation Example 5 Injection An injection having the following composition is prepared by an ordinary method. Compound 3 20 mg Sodium chloride 45 mg To this is added water to make a total volume of 5 ml (for one ampoule). The water was distilled beforehand and sterilized in an autoclave.
【００７３】[0073]
【発明の効果】本発明により、ヌクレオシド輸送阻害活
性を有し、虚血、無酸素症または低酸素症に起因する心
筋障害からの心臓保護に有用な、新規ピペラジン誘導体
またはその薬理的に許容される塩が提供される。Industrial Applicability According to the present invention, a novel piperazine derivative or a pharmacologically acceptable derivative thereof having a nucleoside transport inhibitory activity and useful for cardioprotection from myocardial damage caused by ischemia, anoxia or hypoxia. Salt is provided.
───────────────────────────────────────────────────── フロントページの続き (72)発明者 加瀬 廣 東京都小金井市前原町３−35−18 (72)発明者 鈴木 文夫 静岡県三島市富士見台18の４ 審査官 内藤 伸一 (58)調査した分野(Int.Cl.7，ＤＢ名) C07D 239/94 A61K 31/505 ＣＡ（ＳＴＮ) ＲＥＧＩＳＴＲＹ（ＳＴＮ)──────────────────────────────────────────────────続 き Continued on the front page (72) Inventor Hiroshi Kase 3-35-18 Maeharacho, Koganei-shi, Tokyo (72) Inventor Fumio Suzuki 18-4 Fujimidai, Mishima-shi, Shizuoka Pref. Field (Int. Cl. 7 , DB name) C07D 239/94 A61K 31/505 CA (STN) REGISTRY (STN)
Claims (2)
素、低級アルキル、低級アルコキシ、低級アルカノイ
ル、低級アルコキシカルボニル、カルボキシ、カルバモ
イル、モノまたはジ低級アルキルアミノカルボニル、ト
リフルオロメチル、ヒドロキシ、ハロゲン、ニトロ、ア
ミノ、モノまたはジ低級アルキルアミノまたはシアノを
表し、Ｒ4は水素またはハロゲンを表し、Ｘは水素、カ
ルバモイル、モノまたはジ低級アルキルアミノカルボニ
ル、低級アルコキシカルボニルまたはカルボキシを表
し、ｎは１〜３の整数を表し、Ａｒは置換もしくは非置
換の複素環基を表す）で表されるピペラジン誘導体また
はその薬理的に許容される塩。1. A compound of the formula (I) (Wherein R 1 , R 2 and R 3 are the same or different and are hydrogen, lower alkyl, lower alkoxy, lower alkanoyl, lower alkoxycarbonyl, carboxy, carbamoyl, mono- or di-lower alkylaminocarbonyl, trifluoromethyl, hydroxy Represents halogen, nitro, amino, mono- or di-lower alkylamino or cyano, R 4 represents hydrogen or halogen, X represents hydrogen, carbamoyl, mono- or di-lower alkylaminocarbonyl, lower alkoxycarbonyl or carboxy, n Represents an integer of 1 to 3, and Ar represents a substituted or unsubstituted heterocyclic group) or a pharmaceutically acceptable salt thereof.
その薬理的に許容される塩を含有するアデノシン取り込
み阻害剤。2. An adenosine uptake inhibitor comprising the piperazine derivative according to claim 1 or a pharmaceutically acceptable salt thereof.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP03105593A JP3229693B2 (en) | 1993-02-22 | 1993-02-22 | Piperazine derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP03105593A JP3229693B2 (en) | 1993-02-22 | 1993-02-22 | Piperazine derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH06247942A JPH06247942A (en) | 1994-09-06 |
| JP3229693B2 true JP3229693B2 (en) | 2001-11-19 |
Family
ID=12320803
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP03105593A Expired - Fee Related JP3229693B2 (en) | 1993-02-22 | 1993-02-22 | Piperazine derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP3229693B2 (en) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0882717B1 (en) | 1996-10-01 | 2010-09-08 | Kyowa Hakko Kirin Co., Ltd. | Nitrogenous heterocyclic compounds |
| EP1067123B1 (en) * | 1998-03-31 | 2011-01-19 | Kyowa Hakko Kirin Co., Ltd. | Nitrogenous heterocyclic compounds |
| SE9904738D0 (en) * | 1999-12-22 | 1999-12-22 | Astra Pharma Prod | Novel compounds |
| JP4564713B2 (en) | 2000-11-01 | 2010-10-20 | ミレニアム・ファーマシューティカルズ・インコーポレイテッド | Nitrogen heterocyclic compounds, and methods for making nitrogen heterocyclic compounds and intermediates thereof |
| US6841675B1 (en) * | 2002-06-13 | 2005-01-11 | The Regents Of The University Of California | Piperazine-based nucleic acid analogs |
-
1993
- 1993-02-22 JP JP03105593A patent/JP3229693B2/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| JPH06247942A (en) | 1994-09-06 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP0565546B1 (en) | (-)-[[4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl]-hydrazono]propanedinitrile | |
| EP1319003B1 (en) | Xanthine phosphodiesterase v inhibitors | |
| US5670498A (en) | 8-substituted styryl xanthine derivatives | |
| EP1309594B1 (en) | Benzimidazole derivatives, preparation and therapeutic use thereof | |
| AU2001291022A1 (en) | Xanthine phosphodiesterase v inhibitors | |
| WO2021213317A1 (en) | Hpk1 inhibitor, preparation method therefor and use thereof | |
| TW201831488A (en) | Crystalline forms of (s)-7-(1-(but-2-ynoyl)piperidin-4-yl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide, preparation, and uses thereof | |
| JP2021522201A (en) | Benpyrazole compounds as RHO kinase inhibitors | |
| US20140037538A1 (en) | N-alkyl 2-(disubstituted)alkynyladenosine-5-uronamides as a2a agonists | |
| CN111763215B (en) | A kind of compound with nitrogen-containing heterocyclic structure and preparation method and use thereof | |
| JP3229693B2 (en) | Piperazine derivative | |
| CN110088098B (en) | Quinazolinone PARP-1 inhibitor and preparation method, pharmaceutical composition and application thereof | |
| WO1993003031A1 (en) | Pyrroloazepine derivative | |
| EP0425669B1 (en) | 1-amino-5-halogenouracils, process for their preparation, and central nervous system depressants containing same as active ingredient | |
| CN115124511A (en) | Tacrine derivative, preparation method thereof and application of tacrine derivative as CDK2/9 inhibitor | |
| JPS61215389A (en) | Quinazoline derivative and cardiac containing same | |
| JPH07116188B2 (en) | Novel pyrido [4,3-d] pyrimidine derivative, method for producing the same and pharmaceutical composition containing the compound | |
| JP3252189B2 (en) | Pyrazolo [1,5-a] pyrimidine derivatives | |
| TWI918288B (en) | Phosphate salt of 1-((3s,4r)-3-((2-((1-ethyl-1h-pyrazol-4-yl)amino)-7h-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-4-fluoropiperidin-1-yl)prop-2-en-1-one, crystalline form thereof, and method for preparation thereof | |
| JP2837318B2 (en) | Angiotensin II antagonistic pyridine derivative | |
| KR20250085608A (en) | Phosphate salt of 1-((3S,4R)-3-((2-((1-ethyl-1H-pyrazol-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-4-fluoropiperidin-1-yl)prop-2-en-1-one, crystalline form thereof, and Method for preparation thereof | |
| TW202302587A (en) | Isoquinolinone compound and use thereof | |
| US20170283452A9 (en) | N-alkyl 2-(disubstituted)alkynyladenosine-5-uronamides as a2a agonists | |
| CN117069715A (en) | Multi-substituted pyridine compounds and their preparation methods and applications | |
| TW202535367A (en) | Phosphate salt of 1-((3s,4r)-3-((2-((1-ethyl-1h-pyrazol-4-yl)amino)-7h-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-4-fluoropiperidin-1-yl)prop-2-en-1-one, crystalline form thereof, and method for preparation thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20010828 |
|
| LAPS | Cancellation because of no payment of annual fees |