WO2005063743A1 - チアゾール誘導体 - Google Patents
チアゾール誘導体 Download PDFInfo
- Publication number
- WO2005063743A1 WO2005063743A1 PCT/JP2004/019778 JP2004019778W WO2005063743A1 WO 2005063743 A1 WO2005063743 A1 WO 2005063743A1 JP 2004019778 W JP2004019778 W JP 2004019778W WO 2005063743 A1 WO2005063743 A1 WO 2005063743A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- substituted
- unsubstituted
- heterocyclic group
- alkyl
- aromatic heterocyclic
- Prior art date
Links
- 150000007979 thiazole derivatives Chemical class 0.000 title claims abstract description 91
- 125000006615 aromatic heterocyclic group Chemical group 0.000 claims abstract description 177
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 147
- 150000003839 salts Chemical class 0.000 claims abstract description 131
- 125000006848 alicyclic heterocyclic group Chemical group 0.000 claims abstract description 98
- 125000003710 aryl alkyl group Chemical group 0.000 claims abstract description 67
- 239000002467 adenosine A2a receptor antagonist Substances 0.000 claims abstract description 64
- 125000003107 substituted aryl group Chemical group 0.000 claims abstract description 29
- 239000004480 active ingredient Substances 0.000 claims abstract description 21
- 125000005843 halogen group Chemical group 0.000 claims abstract 2
- -1 5-phosphonofuran 2-yl Chemical group 0.000 claims description 171
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 claims description 155
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 claims description 87
- 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 claims description 84
- 125000003118 aryl group Chemical group 0.000 claims description 68
- 238000000034 method Methods 0.000 claims description 67
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 50
- 239000002126 C01EB10 - Adenosine Substances 0.000 claims description 42
- 229960005305 adenosine Drugs 0.000 claims description 42
- 125000003342 alkenyl group Chemical group 0.000 claims description 41
- 102000005962 receptors Human genes 0.000 claims description 40
- 125000000304 alkynyl group Chemical group 0.000 claims description 39
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 33
- 125000003545 alkoxy group Chemical group 0.000 claims description 31
- 239000003795 chemical substances by application Substances 0.000 claims description 27
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 25
- 238000006467 substitution reaction Methods 0.000 claims description 20
- 208000018737 Parkinson disease Diseases 0.000 claims description 19
- 201000010099 disease Diseases 0.000 claims description 17
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 17
- 125000000623 heterocyclic group Chemical group 0.000 claims description 14
- 125000002541 furyl group Chemical group 0.000 claims description 13
- 229910052736 halogen Inorganic materials 0.000 claims description 12
- 230000001225 therapeutic effect Effects 0.000 claims description 11
- 239000003814 drug Substances 0.000 claims description 9
- 125000002723 alicyclic group Chemical group 0.000 claims description 7
- 208000015114 central nervous system disease Diseases 0.000 claims description 5
- 230000000144 pharmacologic effect Effects 0.000 claims description 5
- 230000003449 preventive effect Effects 0.000 claims description 5
- 230000000069 prophylactic effect Effects 0.000 claims description 5
- 125000005343 heterocyclic alkyl group Chemical group 0.000 claims description 4
- 229940044551 receptor antagonist Drugs 0.000 claims description 4
- 239000002464 receptor antagonist Substances 0.000 claims description 4
- 230000003042 antagnostic effect Effects 0.000 claims description 3
- 229940124597 therapeutic agent Drugs 0.000 claims description 3
- 125000004122 cyclic group Chemical group 0.000 claims description 2
- 235000014113 dietary fatty acids Nutrition 0.000 claims description 2
- 229930195729 fatty acid Natural products 0.000 claims description 2
- 239000000194 fatty acid Substances 0.000 claims description 2
- 102220475869 Keratin, type I cytoskeletal 10_R12A_mutation Human genes 0.000 claims 2
- 125000005055 alkyl alkoxy group Chemical group 0.000 claims 1
- 150000004665 fatty acids Chemical class 0.000 claims 1
- 125000003367 polycyclic group Chemical group 0.000 claims 1
- 229940123702 Adenosine A2a receptor antagonist Drugs 0.000 abstract description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 abstract description 4
- 229910052739 hydrogen Inorganic materials 0.000 abstract description 4
- 125000005346 substituted cycloalkyl group Chemical group 0.000 abstract description 4
- 239000001257 hydrogen Substances 0.000 abstract description 3
- 150000001875 compounds Chemical class 0.000 description 439
- 238000005481 NMR spectroscopy Methods 0.000 description 296
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 252
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 246
- 229940125782 compound 2 Drugs 0.000 description 186
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 166
- 229940125904 compound 1 Drugs 0.000 description 164
- 229940126214 compound 3 Drugs 0.000 description 163
- 239000000243 solution Substances 0.000 description 137
- 238000002844 melting Methods 0.000 description 128
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 128
- 239000007787 solid Substances 0.000 description 127
- 230000008018 melting Effects 0.000 description 126
- 238000006243 chemical reaction Methods 0.000 description 115
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 113
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 112
- 239000002904 solvent Substances 0.000 description 111
- TWBYWOBDOCUKOW-UHFFFAOYSA-N isonicotinic acid Chemical compound OC(=O)C1=CC=NC=C1 TWBYWOBDOCUKOW-UHFFFAOYSA-N 0.000 description 106
- 125000001424 substituent group Chemical group 0.000 description 98
- 239000000203 mixture Substances 0.000 description 96
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 86
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 85
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 84
- JAWMENYCRQKKJY-UHFFFAOYSA-N [3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-ylmethyl)-1-oxa-2,8-diazaspiro[4.5]dec-2-en-8-yl]-[2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidin-5-yl]methanone Chemical compound N1N=NC=2CN(CCC=21)CC1=NOC2(C1)CCN(CC2)C(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F JAWMENYCRQKKJY-UHFFFAOYSA-N 0.000 description 81
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 79
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 61
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 60
- 229910001868 water Inorganic materials 0.000 description 59
- 239000012044 organic layer Substances 0.000 description 58
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 56
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 55
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 51
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 50
- 150000003857 carboxamides Chemical class 0.000 description 49
- 238000010898 silica gel chromatography Methods 0.000 description 48
- 239000002253 acid Substances 0.000 description 42
- 239000011541 reaction mixture Substances 0.000 description 41
- 229910052757 nitrogen Inorganic materials 0.000 description 38
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 36
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 36
- 108020003175 receptors Proteins 0.000 description 35
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 34
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 33
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 31
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 29
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 27
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 27
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 27
- FHKPLLOSJHHKNU-INIZCTEOSA-N [(3S)-3-[8-(1-ethyl-5-methylpyrazol-4-yl)-9-methylpurin-6-yl]oxypyrrolidin-1-yl]-(oxan-4-yl)methanone Chemical compound C(C)N1N=CC(=C1C)C=1N(C2=NC=NC(=C2N=1)O[C@@H]1CN(CC1)C(=O)C1CCOCC1)C FHKPLLOSJHHKNU-INIZCTEOSA-N 0.000 description 27
- 230000008569 process Effects 0.000 description 26
- 125000000437 thiazol-2-yl group Chemical group [H]C1=C([H])N=C(*)S1 0.000 description 26
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 25
- BXDZOYLPNAIDOC-UHFFFAOYSA-N N-[5-[(5-tert-butyl-1,3-oxazol-2-yl)methylsulfanyl]-1,3-thiazol-2-yl]-1-[2-[2-[2-[2-[2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]ethoxy]ethoxy]ethoxy]ethylamino]-2-oxoethyl]piperidine-4-carboxamide Chemical compound CC(C)(C)c1cnc(CSc2cnc(NC(=O)C3CCN(CC(=O)NCCOCCOCCOCCNc4cccc5C(=O)N(C6CCC(=O)NC6=O)C(=O)c45)CC3)s2)o1 BXDZOYLPNAIDOC-UHFFFAOYSA-N 0.000 description 25
- 239000002585 base Substances 0.000 description 25
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 25
- 238000004519 manufacturing process Methods 0.000 description 25
- 229920006395 saturated elastomer Polymers 0.000 description 25
- 239000013078 crystal Substances 0.000 description 24
- 125000003282 alkyl amino group Chemical group 0.000 description 23
- 238000001914 filtration Methods 0.000 description 23
- ABRVLXLNVJHDRQ-UHFFFAOYSA-N [2-pyridin-3-yl-6-(trifluoromethyl)pyridin-4-yl]methanamine Chemical compound FC(C1=CC(=CC(=N1)C=1C=NC=CC=1)CN)(F)F ABRVLXLNVJHDRQ-UHFFFAOYSA-N 0.000 description 22
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 20
- NIPNSKYNPDTRPC-UHFFFAOYSA-N N-[2-oxo-2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 NIPNSKYNPDTRPC-UHFFFAOYSA-N 0.000 description 20
- ZEEBGORNQSEQBE-UHFFFAOYSA-N [2-(3-phenylphenoxy)-6-(trifluoromethyl)pyridin-4-yl]methanamine Chemical compound C1(=CC(=CC=C1)OC1=NC(=CC(=C1)CN)C(F)(F)F)C1=CC=CC=C1 ZEEBGORNQSEQBE-UHFFFAOYSA-N 0.000 description 20
- MZSAMHOCTRNOIZ-UHFFFAOYSA-N 3-[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]oxy-N-phenylaniline Chemical compound NCC1=CC(=NC(=C1)C(F)(F)F)OC=1C=C(NC2=CC=CC=C2)C=CC=1 MZSAMHOCTRNOIZ-UHFFFAOYSA-N 0.000 description 19
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 19
- AFCARXCZXQIEQB-UHFFFAOYSA-N N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CCNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 AFCARXCZXQIEQB-UHFFFAOYSA-N 0.000 description 19
- MMWRGWQTAMNAFC-UHFFFAOYSA-N 1,2-dihydropyridine Chemical compound C1NC=CC=C1 MMWRGWQTAMNAFC-UHFFFAOYSA-N 0.000 description 18
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 18
- REAYFGLASQTHKB-UHFFFAOYSA-N [2-[3-(1H-pyrazol-4-yl)phenoxy]-6-(trifluoromethyl)pyridin-4-yl]methanamine Chemical compound N1N=CC(=C1)C=1C=C(OC2=NC(=CC(=C2)CN)C(F)(F)F)C=CC=1 REAYFGLASQTHKB-UHFFFAOYSA-N 0.000 description 18
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 18
- 235000017557 sodium bicarbonate Nutrition 0.000 description 18
- HAEQAUJYNHQVHV-UHFFFAOYSA-N 3-[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]oxy-N-phenylbenzamide Chemical compound NCC1=CC(=NC(=C1)C(F)(F)F)OC=1C=C(C(=O)NC2=CC=CC=C2)C=CC=1 HAEQAUJYNHQVHV-UHFFFAOYSA-N 0.000 description 17
- 125000004433 nitrogen atom Chemical group N* 0.000 description 17
- 238000012360 testing method Methods 0.000 description 17
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 16
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 16
- 150000002576 ketones Chemical group 0.000 description 16
- 238000010992 reflux Methods 0.000 description 16
- GDSLUYKCPYECNN-UHFFFAOYSA-N 3-[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]oxy-N-[(4-fluorophenyl)methyl]benzamide Chemical compound NCC1=CC(=NC(=C1)C(F)(F)F)OC=1C=C(C(=O)NCC2=CC=C(C=C2)F)C=CC=1 GDSLUYKCPYECNN-UHFFFAOYSA-N 0.000 description 15
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 15
- KXDAEFPNCMNJSK-UHFFFAOYSA-N benzene carboxamide Natural products NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 15
- 230000027455 binding Effects 0.000 description 15
- JWHOQZUREKYPBY-UHFFFAOYSA-N rubonic acid Natural products CC1(C)CCC2(CCC3(C)C(=CCC4C5(C)CCC(=O)C(C)(C)C5CC(=O)C34C)C2C1)C(=O)O JWHOQZUREKYPBY-UHFFFAOYSA-N 0.000 description 15
- HMUNWXXNJPVALC-UHFFFAOYSA-N 1-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]-2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)C(CN1CC2=C(CC1)NN=N2)=O HMUNWXXNJPVALC-UHFFFAOYSA-N 0.000 description 14
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 14
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 14
- FFBHFFJDDLITSX-UHFFFAOYSA-N benzyl N-[2-hydroxy-4-(3-oxomorpholin-4-yl)phenyl]carbamate Chemical compound OC1=C(NC(=O)OCC2=CC=CC=C2)C=CC(=C1)N1CCOCC1=O FFBHFFJDDLITSX-UHFFFAOYSA-N 0.000 description 14
- 238000004587 chromatography analysis Methods 0.000 description 14
- 238000010438 heat treatment Methods 0.000 description 14
- RMIODHQZRUFFFF-UHFFFAOYSA-N methoxyacetic acid Chemical compound COCC(O)=O RMIODHQZRUFFFF-UHFFFAOYSA-N 0.000 description 14
- SIOXPEMLGUPBBT-UHFFFAOYSA-N picolinic acid Chemical compound OC(=O)C1=CC=CC=N1 SIOXPEMLGUPBBT-UHFFFAOYSA-N 0.000 description 14
- WZZBNLYBHUDSHF-DHLKQENFSA-N 1-[(3s,4s)-4-[8-(2-chloro-4-pyrimidin-2-yloxyphenyl)-7-fluoro-2-methylimidazo[4,5-c]quinolin-1-yl]-3-fluoropiperidin-1-yl]-2-hydroxyethanone Chemical compound CC1=NC2=CN=C3C=C(F)C(C=4C(=CC(OC=5N=CC=CN=5)=CC=4)Cl)=CC3=C2N1[C@H]1CCN(C(=O)CO)C[C@@H]1F WZZBNLYBHUDSHF-DHLKQENFSA-N 0.000 description 13
- 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 13
- 229940125898 compound 5 Drugs 0.000 description 13
- 238000000354 decomposition reaction Methods 0.000 description 13
- VFQXVTODMYMSMJ-UHFFFAOYSA-N isonicotinamide Chemical compound NC(=O)C1=CC=NC=C1 VFQXVTODMYMSMJ-UHFFFAOYSA-N 0.000 description 13
- 239000012046 mixed solvent Substances 0.000 description 13
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 12
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 12
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 11
- DEXFNLNNUZKHNO-UHFFFAOYSA-N 6-[3-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperidin-1-yl]-3-oxopropyl]-3H-1,3-benzoxazol-2-one Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C1CCN(CC1)C(CCC1=CC2=C(NC(O2)=O)C=C1)=O DEXFNLNNUZKHNO-UHFFFAOYSA-N 0.000 description 11
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 11
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 11
- 150000002367 halogens Chemical group 0.000 description 11
- 125000006239 protecting group Chemical group 0.000 description 11
- 239000008096 xylene Substances 0.000 description 11
- GOJUJUVQIVIZAV-UHFFFAOYSA-N 2-amino-4,6-dichloropyrimidine-5-carbaldehyde Chemical group NC1=NC(Cl)=C(C=O)C(Cl)=N1 GOJUJUVQIVIZAV-UHFFFAOYSA-N 0.000 description 10
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 description 10
- GQHTUMJGOHRCHB-UHFFFAOYSA-N DBU Substances C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 10
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 10
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 10
- 125000004457 alkyl amino carbonyl group Chemical group 0.000 description 10
- 239000000499 gel Substances 0.000 description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 description 10
- YIWGJFPJRAEKMK-UHFFFAOYSA-N 1-(2H-benzotriazol-5-yl)-3-methyl-8-[2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carbonyl]-1,3,8-triazaspiro[4.5]decane-2,4-dione Chemical compound CN1C(=O)N(c2ccc3n[nH]nc3c2)C2(CCN(CC2)C(=O)c2cnc(NCc3cccc(OC(F)(F)F)c3)nc2)C1=O YIWGJFPJRAEKMK-UHFFFAOYSA-N 0.000 description 9
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 9
- MKYBYDHXWVHEJW-UHFFFAOYSA-N N-[1-oxo-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propan-2-yl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(C(C)NC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 MKYBYDHXWVHEJW-UHFFFAOYSA-N 0.000 description 9
- 235000019270 ammonium chloride Nutrition 0.000 description 9
- 125000002950 monocyclic group Chemical group 0.000 description 9
- 238000003756 stirring Methods 0.000 description 9
- 239000000126 substance Substances 0.000 description 9
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- 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
- XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical compound C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- KNCYXPMJDCCGSJ-UHFFFAOYSA-N piperidine-2,6-dione Chemical compound O=C1CCCC(=O)N1 KNCYXPMJDCCGSJ-UHFFFAOYSA-N 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- VDVJGIYXDVPQLP-UHFFFAOYSA-M piperonylate Chemical compound [O-]C(=O)C1=CC=C2OCOC2=C1 VDVJGIYXDVPQLP-UHFFFAOYSA-M 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 239000011698 potassium fluoride Substances 0.000 description 1
- 235000003270 potassium fluoride Nutrition 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 229960003857 proglumide Drugs 0.000 description 1
- WGYKZJWCGVVSQN-UHFFFAOYSA-O propan-1-aminium Chemical compound CCC[NH3+] WGYKZJWCGVVSQN-UHFFFAOYSA-O 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- WHMDPDGBKYUEMW-UHFFFAOYSA-N pyridine-2-thiol Chemical compound SC1=CC=CC=N1 WHMDPDGBKYUEMW-UHFFFAOYSA-N 0.000 description 1
- QJZUKDFHGGYHMC-UHFFFAOYSA-N pyridine-3-carbaldehyde Chemical compound O=CC1=CC=CN=C1 QJZUKDFHGGYHMC-UHFFFAOYSA-N 0.000 description 1
- GZRKXKUVVPSREJ-UHFFFAOYSA-N pyridinylpiperazine Chemical compound C1CNCCN1C1=CC=CC=N1 GZRKXKUVVPSREJ-UHFFFAOYSA-N 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- 150000003283 rhodium Chemical class 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 210000002460 smooth muscle Anatomy 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- SRWFBFUYENBCGF-UHFFFAOYSA-M sodium;chloride;hydrochloride Chemical compound [Na+].Cl.[Cl-] SRWFBFUYENBCGF-UHFFFAOYSA-M 0.000 description 1
- 239000008279 sol Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 210000003523 substantia nigra Anatomy 0.000 description 1
- 229960002317 succinimide Drugs 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 125000006633 tert-butoxycarbonylamino group Chemical group 0.000 description 1
- 125000003039 tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 description 1
- 125000005942 tetrahydropyridyl group Chemical group 0.000 description 1
- 125000000147 tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000005458 thianyl group Chemical group 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- QIQITDHWZYEEPA-UHFFFAOYSA-N thiophene-2-carbonyl chloride Chemical group ClC(=O)C1=CC=CS1 QIQITDHWZYEEPA-UHFFFAOYSA-N 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 125000005628 tolylene group Chemical group 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- OSIQUECDJCZFED-UHFFFAOYSA-N tributyl-(2-methoxyphenyl)stannane Chemical compound CCCC[Sn](CCCC)(CCCC)C1=CC=CC=C1OC OSIQUECDJCZFED-UHFFFAOYSA-N 0.000 description 1
- LIILCIIZVMZTSC-UHFFFAOYSA-N tributyl-(4-methoxyphenyl)stannane Chemical compound CCCC[Sn](CCCC)(CCCC)C1=CC=C(OC)C=C1 LIILCIIZVMZTSC-UHFFFAOYSA-N 0.000 description 1
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- A61K31/425—Thiazoles
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- A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
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- A61K31/472—Non-condensed isoquinolines, e.g. papaverine
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- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
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- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
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- C07D513/04—Ortho-condensed systems
Definitions
- the present invention relates to an adenosine A 2A receptor antagonist containing, for example, a thiazole derivative or a pharmacologically acceptable salt thereof as an active ingredient.
- Background Art It is known that adenosine is widely distributed in the living body and exhibits various physiological actions on the central nervous system, myocardium, kidney, lung, smooth muscle and the like through its receptor. To date, four subtypes of Ai, A 2 A, A 2B and A 3 have been found for adenosine receptors. Subtype-selective antagonists and agonists of each receptor are expected to exert their pharmacological effects based on the biological significance of the subtype and its distribution in the body.
- the A 2A receptor is localized in the striatum in the brain, and one of its functions has been reported to suppress the release of neurotransmitters [ ⁇ mouth pian * European Journal of Pharmacology, 168th, ⁇ ⁇ 285 (1989)].
- antagonists to the adenosine A 2A receptor include, for example, Parkinson's disease, Alzheimer's disease, progressive supranuclear palsy, AIDS encephalopathy, spread spongiform encephalopathy, multiple sclerosis, amyotrophic lateral sclerosis Huntington's disease, multiple system atrophy, cerebral ischemia, attention deficit hyperactivity disorder, sleep disorder, ischemic heart disease, intermittent claudication, diabetes, anxiety disorder (panic attacks and panic disorders, phobias, threatening Disorders, post-traumatic stress disorder, acute stress disorder, generalized anxiety disorder, physical or substance anxiety, etc.), mood disorders (such as depression, mood modulation disorders, mood circulatory disorders), restlessness syndrome (RLS>, drug addiction (alcoholism etc.), eating disorders, epilepsy, migraine, treatment of a disease the adenosine a 2A receptor, such as chronic musculoskeletal pain is involved and Z or
- many compounds are known as compounds having a thiazole skeleton (for
- Patent application referenced Publication No. 2004-0053982 discloses thiazole derivative conductors having adenosine receptor antagonism and adenosine a 2A receptor antagonistic activity.
- thiazole derivatives having a furyl group at the 4-position are known (US Pat. No. 6489476, WO02 / 03978, WO01 / 47935, WO00 / 38666, WO00 / 14095, “Chemistry”.
- R is phenylmethinole, 2-furyl, 4-fluorophenol-nore, 2-fluorophenenore, 2,4-dichlorophenol-nore, 4-12 trofeninore, 2-two-trofenenore, 4-bromophenenole , 3-Bromophenol, 2-Bromophenol, 2-Chronophenol, 3-Bromo-2-methoxyphenyl, 4-1 tert-Butylphenyl, 3-methylphenyl, 4-Methylphenol, 4-
- the thiazole derivatives represented by the above general formula (A) are registered as chemical libraries in the CAS Registry Database (CAS REGISTRY Database). Have
- An object of the present invention is to have an adenosine A 2A receptor antagonist, an adenosine A 2A receptor antagonistic action containing, for example, a thiazole derivative or a pharmacologically acceptable salt thereof as an active ingredient, It is intended to provide a thiazole derivative or a pharmacologically acceptable salt thereof useful for the treatment and / or prevention of various diseases involving adenosine A 2A receptor.
- the present invention relates to the following (1) to (: 118).
- n an integer of 0 to 3
- R 1 is substituted or unsubstituted cycloalkyl
- R2 is halogen
- R 5 and R 6 are the same or different
- R 7 is a hydrogen atom
- R8 is a hydrogen atom
- Substituted or non-substituted aryl, '-Substitution is also an unsubstituted aralkyl
- Substituted Migaku is an unsubstituted aromatic heterocyclic group
- R 9 and are the same or different
- RH is a hydrogen atom
- R3 and R4 are the same or different
- R12 is a hydrogen atom
- R13 and RW are the same or different
- R 15 is a hydrogen atom
- a substituted or non-substituted aryl is substituted or non-substituted aryl.
- R2 is not a substituted or unsubstituted 6-oxo-1, '6-dihydropyridazine 3-yl ⁇
- An adenosine A2A receptor antagonist comprising the thiazole derivative represented by the formula (I) or a pharmacologically acceptable salt thereof as an active ingredient.
- Ri is adenosine A 2A receptor antagonist of the above-mentioned (1), wherein the substituted or unsubstituted Ariru or substituted or unsubstituted aromatic double ring group.
- adenosine A 2A receptor antagonist of the above-mentioned (1) wherein the Ri is a substituted or unsubstituted 5-membered aromatic heterocyclic group.
- Ri is a substituted or unsubstituted 5-membered ring aromatic containing at least one oxygen atom
- R 2 is substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl, substituted or unsubstituted alicyclic heterocyclic group, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted fat
- adenosine A 2A receptor according to any one of (1) to (8), wherein R 2 is a substituted or unsubstituted alicyclic heterocyclic group or a substituted or unsubstituted aromatic heterocyclic group. Antagonists.
- R8 is a hydrogen atom, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl , Substituted or unsubstituted aralkyl, substituted or unsubstituted alicyclic heterocyclic group, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted alicyclic heterocyclic alkyl, or substituted or unsubstituted
- the adenosine A2A receptor antagonist according to any one of the above (1) to (9) and (14), which is an aromatic heterocyclic alkyl.
- R 8 is a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted alicyclic heterocyclic group or a substituted or unsubstituted aromatic heterocyclic group
- R 8 is a substituted or unsubstituted aryl, a substituted or unsubstituted alicyclic heterocyclic group or a substituted or unsubstituted aromatic heterocyclic group
- the adenosine A2A receptor antagonist according to any one of the above. '
- R8 is Ariru substituted or unsubstituted (1) to (9) and the adenosine A 2A receptor antagonist in any crab described (14).
- adenosine A 2A receptor antagonist according to any one of the above R 8 is a substituted or unsubstituted alicyclic heterocyclic group (1) to (9) and (14).
- R3 is adenosine A 2A receptor antagonist according to any one of the above lower alkyl or Ararukiru (1) to (21).
- R 4 is COR 12a (where Ri 2a is substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkoxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl) , Substituted or unsubstituted aralkyl quinole, substituted or unsubstituted alicyclic heterocyclic group, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted alicyclic bicyclic alkyl or substituted or unsubstituted aromatic Adenosine A 2A receptor antagonist according to the above (22) or (23).
- R 4 force S—CORi 2d (wherein R 12d represents a substituted or unsubstituted aryl, substituted or unsubstituted alicyclic heterocyclic group or substituted or unsubstituted aromatic heterocyclic group. (22) or (23), the adenosine A 2A receptor antagonist.
- R 4 is COR g [wherein R 1 is substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkoxy, substituted or unsubstituted alkyl, substituted or unsubstituted '(But not "the substitution site of the substituent in the substituted aryl" and “the binding site of 111 and -00-" in 100111) are not adjacent), substituted or unsubstituted aralkyl (However, "the substitution site of the substituent in the aryl moiety of the substituted aralkyl” and “the site where the alkyl part of the aralkyl binds to the aryl moiety" are not adjacent), a substituted or unsubstituted alicyclic heterocycle A cyclic group, a substituted or non-substituted aromatic heterocyclic group (provided that “the substitution site of the substituent in the substituted aromatic heterocyclic group”),
- the bonding site between Ri ⁇ and 1 CO- in one CORi is not adjacent to each other), substituted or unsubstituted alicyclic heterocyclic alkyl or substituted or unsubstituted aromatic heterocyclic alkyl (provided that The substitution site of the substituent in the aromatic heterocyclic part of the substituted aromatic heterocyclic alkyl "and the" site where the alkynole part of the aromatic heterocyclic alkyl binds to the aromatic heterocyclic part "are not adjacent.
- the adenosine A 2A receptor antagonist according to the above (22) or (23).
- R 3 and R 4 are the same or different and each has the same meaning as defined above.
- the adenosine A 2A receptor receptor agent according to any one of (1) to (21) above.
- n 0 and Ri contains at least one substituted or unsubstituted oxygen atom
- Adenosine A 2A receptor antagonist according to (1) above which is a 5-membered aromatic heterocyclic group, and R 2 is — CORSa (wherein RSa represents a substituted or unsubstituted alicyclic heterocyclic group) Agent.
- Ri is Furinre substituted or unsubstituted above (43) according adenosine A 2A receptor antagonist o
- the R 8 a is aliphatic heterocyclic group containing at least one oxygen atom of a substituted or unsubstituted (43) or (44) adenosine A 2A receptor antagonist according.
- R 3 is a hydrogen atom
- R 4 is a substituted or unsubstituted lower aralkyl, .substituted or unsubstituted aralkyl, or a substituted or unsubstituted aromatic heteroalkyl, the above (1) to ( 21) and the adenosine A2A receptor antagonist according to any one of (43) to (45).
- R 1A is a 5-membered aromatic heterocyclic group containing at least one substituted or unsubstituted oxygen atom (excluding a group selected from 5-phosphonofuran 2-yl and 5-nitrofuran 1-2-yl). ) '
- Ri 2 and n are as defined above,
- R 3A is a hydrogen atom
- R 2 A is substituted or unsubstituted lower alkyl
- R2 is substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl, substituted or unsubstituted alicyclic heterocyclic group, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted alicyclic ring
- R 8 is a hydrogen atom, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl, substituted or unsubstituted cycloanolyl, substituted or unsubstituted aryl, substituted Or an unsubstituted aralkyl quinole, a substituted or unsubstituted alicyclic heterocyclic group, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted alicyclic heterocyclic alkyl or a substituted or unsubstituted aromatic
- the thiazole derivative according to the above (60) which is a group heterocyclic alkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl, substituted or unsubstituted cycloanolyl, substituted or unsub
- R 8 is substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted alicyclic heterocyclic group or substituted or unsubstituted aromatic heterocyclic group Or a pharmacologically acceptable salt thereof.
- R 8 is substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted Alternatively, an unsubstituted alicyclic heterocyclic group or a substituted or unsubstituted aromatic heterocyclic group (provided that a substituted or non-substituted aromatic group having a nitrogen atom and bonded to one COR 8 —CO— by the nitrogen atom)
- R 12 A is substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkoxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted (74) a substituted alicyclic heterocyclic group, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted alicyclic heterocyclic alkyl, or a substituted or unsubstituted aromatic heterocyclic alkyl
- the described thiazole derivative or a pharmaceutically acceptable salt thereof is substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkoxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubsti
- R12A is substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkoxy, substituted or unsubstituted cycl, mouth alkyl, substituted or unsubstituted aryl (but the substitution of substituents in the substituted aryl) Part ”and“ one in COR 12A And one CO— binding site ”are not adjacent), substituted or unsubstituted aralkyl
- substitution site of the substituent in the aryl moiety of the substituted aralkyl and “the site where the alkyl moiety of the aralkyl binds to the aryl moiety” are not adjacent
- a substituted or unsubstituted alicyclic ring Heterocyclic group, substituted or unsubstituted aromatic heterocyclic group are not adjacent to each other
- substituted or unsubstituted alicyclic bicyclic alkyl or substituted or unsubstituted aromatic heterocyclic alkyl are not adjacent to each other
- substituted or unsubstituted alicyclic bicyclic alkyl or substituted or unsubstituted aromatic heterocyclic alkyl are not adjacent to each other
- substituted or unsubstituted alicyclic bicyclic alkyl or substituted or unsubstituted aromatic heterocyclic alkyl are not adjacent to each other
- R12 is substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkoxy, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted
- the thiazole sol derivative or a pharmacologically acceptable salt thereof according to any one of (84).
- R12 is substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkoxy, substituted or unsubstituted alkyl, substituted or unsubstituted aryl (but the substitution site of the substituent in the substituted aryl) ”And“ the binding site of R 12 and one CO— in one COR 12 ”are not adjacent to each other), substituted or unsubstituted aralkyl (however,“ substitution site of the substituent in the aryl moiety of the substituted aralkyl ” ”And“ site where the alkyl moiety of the aralkyl is bonded to the aryl moiety ”), a substituted or unsubstituted alicyclic heterocyclic group, a substituted or unsubstituted aromatic heterocyclic group (However,
- substitution site of the substituent in the substituted aromatic heterocyclic group and “bonding site between Ri 2 and 1 CO- in one CORi 2 " are not adjacent), substituted or unsubstituted alicyclic Heterocyclic alkyl or substituted or unsubstituted aromatic heterocyclic alkyl (where “the substitution site of the substituent in the aromatic heterocyclic portion of the substituted aromatic heterocyclic alkyl” and “the alkyl portion of the aromatic heterocyclic alkyl is The thiazole derivative or the pharmaceutically acceptable salt thereof according to any one of the above (52) to (84), which is not adjacent to the “site bonded to the aromatic heterocyclic moiety”.
- n and RiA are as defined above,
- R 3B is a hydrogen atom, ...
- R 4 B is substituted or unsubstituted lower alkyl
- R 8B is a hydrogen atom
- a medicament comprising as an active ingredient the thiazole derivative according to any one of (52) to (103) or a pharmacologically acceptable salt thereof.
- An adenosine A2A receptor antagonist comprising, as an active ingredient, the thiazole derivative according to any one of (52) to (103) or a pharmacologically acceptable salt thereof.
- adenosine A 2A diseases receptor which comprises, as a thiazole derivative or active ingredient thereof a pharmacologically acceptable salt thereof according to any one of the therapeutic and / or Preventive agent.
- a therapeutic and / or preventive agent for central nervous disease comprising the thiazonole derivative or a pharmaceutically acceptable salt thereof according to any one of (52) to (103) as an active ingredient.
- a therapeutic or therapeutic agent for Parkinson's disease comprising the thiazole derivative according to any of the above (52) to (103) or a pharmaceutically acceptable salt thereof as an active ingredient. Agent.
- n, R 2 , R 3 and R 4 are as defined above
- an effective amount of a thiazol derivative represented by the formula or a pharmaceutically acceptable salt thereof is administered.
- a treatment for central nervous disease characterized by administering an effective amount of the thiazole derivative according to any of (52) to (103) above or a pharmacologically acceptable salt thereof, or Z or Prevention method.
- n, -RK H 2 , R 3 and R 4 are as defined above
- a pharmacologically acceptable salt thereof
- alkyl having 1 to 10 carbon atoms such as methyl, ethynole, propyl, isopropyl, butinole, isobutinole, sec-petitenole, tert-butyl, pentinole, isopentinole, neopentinole, hexyl, heptyl, octyl, nonyl, Decyl etc.-
- Lower alkenyl includes, for example, linear or branched alkenyl having 2 to 10 carbon atoms, and specifically, bur, aryl, 1-propenyl, ptur, pentenyl, hexenyl, heptul. , Otatur, nonenyl, decenyl and the like.
- Lower alkynyl includes, for example, straight-chain or branched alkynyl having 2 to 10 carbon atoms, and specifically includes ethynyl, probule, butur, pentul, hex Le, heptul, otachuru, noninyl, decynyl, etc.
- cycloalkyl examples include cycloalkyl having 3 to 8 carbon atoms, and specific examples include cyclopropyl, cyclobutynole, cyclopentinole, cyclohexyl, cyclopentyl, cyclooctyl and the like. '
- the aryl moiety of aryl and aralkyl includes, for example, aryl having 6 to 10 carbon atoms, and specifically includes phenyl, naphthyl and the like.
- the aromatic heterocyclic group part of the aromatic heterocyclic group, aromatic heterocyclic alkyl and aromatic heterocyclic methyl is, for example, at least one selected from a nitrogen atom, an oxygen atom and a sulfur atom.
- Specific examples include furyl, phenyl, pyrrolyl, pyridyl, N-oxopyridyl, pyrazinyl, imidazolyl, pyrazolyl, triazolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, and the like.
- the monocyclic aromatic heterocyclic group includes, for example, the 5-membered or 6-membered monocyclic aromatic heterocyclic group exemplified in the above-mentioned aromatic heterocyclic group (vi), specifically, Furyl, chenyl, pyrrolyl, pyridyl, N-oxopyridyl, pyrazinyl, imidazolyl, pyrazolyl, triazolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isooxazolyl, oxadiazolyl, pyrimidinyl, pyrididinyl, etc.
- Examples of the 5-membered aromatic heterocyclic group include the 5-membered monocyclic aromatic heterocyclic groups exemplified in the above-mentioned monocyclic aromatic heterocyclic group (vii), and specifically Examples include furyl, chael, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, and oxadiazolyl.
- the 5-membered aromatic heterocyclic group containing at least one oxygen atom for example, among the 5-membered monocyclic aromatic heterocyclic ring exemplified in the above-mentioned 5-membered aromatic heterocyclic group (viii) Examples thereof include a 5-membered monocyclic aromatic heterocyclic group containing at least one oxygen atom, and specifically include furyl, oxazolyl, isoxazolyl, oxaziazolyl and the like.
- the alicyclic heterocyclic group part of the alicyclic heterocyclic group, the alicyclic heterocyclic alkyl and the alicyclic heterocyclic methyl is, for example, at least selected from a nitrogen atom, an oxygen atom and a sulfur atom.
- Examples of the alicyclic heterocyclic group containing at least one oxygen atom include the alicyclic heterocyclic groups containing at least one oxygen atom exemplified in the above alicyclic heterocyclic group (X). Morpholinol, morpholino, oxazolinyl, dioxolanil, dioxanyl, dioxepannole, vilaninole, dihydropyranyl, tetrahydroviral, talented kuta hydrovirazino [1, 4] [1, 4] Oxazininole, oxyrael, oxetanyl, oxolanil, perhydroxazepinyl, 1,3-benzodioxolinole, 1,4 benzodioxannole, 3,4-dihydro 2H-1, 5-Benzodioxepinyl, 1,4-dioxaspiro [4.5] Decanyl, 1,4-dioxar 8
- heterocyclic group having a nitrogen atom and bonded to one CO— of one COR 8 by the nitrogen atom for example, a 5-membered or 6-membered monocyclic heterocyclic group containing at least one nitrogen atom (The monocyclic heterocyclic group may contain other nitrogen atom, oxygen atom or sulfur atom), 3 to 8 A condensed or heterocyclic group containing at least one nitrogen atom fused to a member ring (this condensed heterocyclic group may be another nitrogen * atom, oxygen atom or sulfur atom).
- pyrrolyl 1-pyrrolidinyl, morpholino, thiomorpholino, 1-virazolidinyl, piperidino, 1 piperazinyl, 1-homopiperazinole, 1 aziridininole
- examples include 1-azetidinyl, 1-azolidinyl, 1-perhydroazepinyl, and 1-perhydrocarbazosinyl.
- alkylene portion of aralkyl, aromatic heterocyclic alkyl and alicyclic heterocyclic alkyl examples include linear or branched alkylene having 1 to 10 carbon atoms, specifically, And those obtained by removing one hydrogen atom from the group exemplified for lower alkyl (i).
- Halogen means each atom of fluorine, chlorine, bromine and iodine.
- Substituents (A) in the substituted lower alkyl may be the same or different, for example, substituents of! To 3; specifically, halogen, hydroxy, nitro, azide, amino, cyan, Carboxy, formyl, substituted or unsubstituted lower alkoxy, substituted or unsubstituted lower alkyloxy, substituted or unsubstituted lower alkylsulfanyl, substituted or unsubstituted lower alkylamino, substituted or unsubstituted di-lower alkylamino, Examples thereof include substituted or unsubstituted adamantylamino, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryloxy, substituted or unsubstituted bicyclic oxy and the like.
- the substituent (a) in the substituted lower alkoxy, substituted lower alkanoyloxy, substituted lower alkylsulfinyl, substituted lower alkylamino and substituted dilower alkylamino exemplified in the substituent (A) may be the same or different, for example, the number of substitutions.
- substituents such as halogen, hydroxy, hydroxyimino, methoxyimino, nitrite, azide, amino, cyano, carboxy, cycloalkyl, substituted or unsubstituted lower alkoxy, substituted or non-substituted Substituted substituted lower alkanoyloxy, substituted or unsubstituted lower alkylamino, substituted or unsubstituted ⁇ di-lower alkylamino, substituted or unsubstituted aryl, substituted or unsubstituted alicyclic heterocyclic group, substituted or unsubstituted Substituted aromatic heterocyclic group, aryloxy, heterocyclic And the like.
- substituents such as halogen, hydroxy, hydroxyimino, methoxyimino, nitrite, azide, amino, cyano, carboxy, cycloalkyl, substituted or unsubstituted lower alkoxy, substitute
- the substituent (b) in the substituted lower alkoxy, substituted lower alkanoyloxy, substituted lower alkylamino and substituted dilower alkylamino exemplified in the substituent (a) may be the same or different, for example, the number of substitutions:!
- the substituent (c) in the substituted aryl and substituted aromatic heterocyclic group exemplified in the substituent (a) may be the same or different, for example, the number of substitutions:!
- substituents in the substituted alicyclic heterocyclic group exemplified in the substituent (a) may be the same or different and include, for example, a substituent having 1 to 3 substituents, specifically exemplified by the substituent (b).
- substituent (e) may be the same or different, for example, a substituent having 1 to 3 substituents. Specific examples include lower alkyl, lower alkoxy, hydroxy, oxo, formyl, etc.
- the substituents () in the substituted cycloalkyl exemplified in the substituent (A) are the same or different.
- the number of substituents:! To 3 is exemplified, and specific examples include the group exemplified in the substituent (a), lower alkyl, lyso, formyl, etc.
- substituted heterocyclic oxy Examples of the substituent (g) in are the same or different and include, for example, substituents having the number of substitutions:!
- halogen hydroxy, nitro, azide, amino, cyano, carboxy, formyl, substituted or Unsubstituted lower alkyl, substituted or unsubstituted lower alkanol, cycloalkynole, lower alkoxy, lower alkylsulfanyl, lower alkylsulfonyl, lower alkoxycarbonyl, lower alkylaminocarbonyl, di-lower alkylaminocarbonyl, lower alkylamino, di-lower alkylamino, And arylene, alicyclic heterocyclic group, aromatic heterocyclic group, aryloxy, heterocyclic oxy, etc.
- Substituents in the substituted lower alkyl and substituted lower alkyl groups exemplified in Substituent (g) are as follows: The same or different Examples of the substituent include 1 to 3 substituents, specifically, the groups exemplified in the substituent (b), etc.
- the aryl moiety, the alicyclic heterocyclic group, the aromatic heterocyclic group, and the halogen are the above-mentioned lower alkyl (i), cycloalkyl, respectively.
- Substituent (B) in substituted lower alkyl, substituted lower alkenyl, substituted lower alkynyl and substituted lower alkoxy may be the same or different, for example, a substituent having 1 to 3 substituents, specifically Examples thereof include a group exemplified for the substituent (A), a substituted or unsubstituted aryl, a substituted or unsubstituted alicyclic heterocyclic group, a substituted or unsubstituted aromatic heterocyclic group, and the like.
- Examples of the substituent (h) in the substituted aryl and the substituted aromatic heterocyclic group exemplified in the substituent (B) are the same or different, for example, a substituent having 1 to 3 substituents. Examples thereof include the groups exemplified in the group (a), lower alkyl and the like. Examples of the substituent j) in the substituted alicyclic heterocyclic group exemplified in the substituent (B) include the same or different substituents having, for example, 1 to 3 substituents. Specifically, in the substituent (a), Examples thereof include lower alkyl, lower alkyl, formaldehyde, and formyl.
- the lower alkyl, aryl, alicyclic heterocyclic group and aromatic heterocyclic group exemplified in the substituent (B), substituent (h) and substituent (j) are the same as the lower alkyl (i), aryl ( v), synonymous with alicyclic heterocyclic group (X) and aromatic heterocyclic group (vi).
- Substituents (C) in the substituted cycloalkyl are the same or different and include, for example, substituents having 1 to 3 substituents, specifically, the groups exemplified in the substituent (A), lower alkyl, oxo Etc.
- the lower alkyl exemplified for the substituent (C) has the same meaning as the aforementioned lower alkyl (i).
- Substituted lower alkylsulfonyl, substituted lower alkylaminosulfonyl, substituted di-lower alkylaminosulfonyl, substituted lower alkoxycarbonyl, substituted lower alkylamino force sulfonyl and substituted di-lower alkylaminocarbonyl are the same or different, for example, Examples of the substituent include 1 to 3 substituents, and specific examples thereof include the groups exemplified in the substituent (a).
- Examples of the substituent in the substituted aryl, substituted aryloxy, substituted aromatic heterocyclic group and substituted heterocyclic group exemplified in the substituent (D) are the same or different, and examples thereof include a substituent having 1 to 3 substituents. Specific examples include groups exemplified for the substituent (g). Examples of the substituent (k) in the substituted cycloalkyl exemplified in the substituent (D) and the substituted alicyclic heterocyclic group are the same or different, and examples thereof include a substituent having 1 to 3 substituents. Examples thereof include the groups exemplified for the substituent (a), lower alkyl, and oxo.
- Lower alkyl, lower alkyl, lower alkoxy, lower alkanoyloxy, lower alkylamino, di-lower alkylsulfamino, lower alkylsulfanyl, lower alkylsulfonyl, lower alkyl exemplified for substituent (D) and substituent (k) Aminosulfonyl, di-lower alkylaminosulfonyl, lower alkoxycarbonyl, lower alkylaminocarbonyl, di-lower alkylaminocarbonyl and lower alkyl moiety of tri (lower alkyl) silyl, lower alkenyl, lower alkynyl, cycloalkyl, aryl And the aryl moiety of the aryloxy group, the alicyclic heterocyclic group, the aromatic heterocyclic group, and the halogen are the above-mentioned lower alkyl (i), lower alkenyl (ii), lower alkynyl (iii
- substituent (E) in substituted alicyclic heterocyclic groups, substituted alicyclic heterocyclic groups containing at least one oxygen atom, substituted tetrahydrobilanyl, substituted alicyclic heterocyclic alkyl and substituted alicyclic heterocyclic methyl
- substituent (E) are the same or different and include, for example, substituents having the number of substitutions:! To 3, and specific examples include the group exemplified by the substituent (D) and oxo.
- the pharmacologically acceptable salts of compound (I) include, for example, pharmacologically acceptable acid addition salts, metal salts, ammonium salts, organic amine addition salts, amino acid addition salts and the like.
- Examples of the pharmacologically acceptable acid addition salt of compound (I) include inorganic acid salts such as hydrochloride, sulfate, and phosphate, acetate, maleate, fumarate, and kenate.
- Examples of the pharmacologically acceptable metal salts include alkali metal salts such as sodium salt and strength rhodium salt, alkaline earthing metal salts such as magnesium salt and calcium salt, aluminum, and the like.
- Examples of the pharmacologically acceptable ammonium salt include salts such as ammonium and tetramethylamine, and pharmaceutically acceptable organic amine addition salts. Examples include addition salts such as morpholine and piperidine.
- Examples of pharmacologically acceptable amino acid addition salts include lysine, glycine, phenylalanine, and asparagine.
- Addition salts such as glutamic acid is raised, et al.
- the adenosine A 2A diseases ⁇ Denoshin A 2A receptors are involved which are by connexion treatment
- Contact Yopi or prevention receptor antagonist of the present invention such as Parkinson's disease, Aruhhaima one disease, progressive supranuclear palsy, AIDS Encephalopathy, spread spongiform encephalopathy, multiple sclerosis, amyotrophic lateral sclerosis, Huntington's disease, multiple system atrophy, cerebral ischemia, attention deficit hyperactivity disorder, sleep disorder, ischemic heart disease, Intermittent claudication, diabetes, anxiety disorders (such as panic attacks and panic disorders, phobias, threatening disorders, post-traumatic stress disorder, acute stress disorder, generalized anxiety disorder, physical disability or anxiety due to substance), mood Disorders (depression, dysthy
- R 3 and R 4 are hydrogen atoms (Ia), R 3 is a hydrogen atom, R 4 is a substituted or unsubstituted lower alkyl, substituted or Unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aromatic heterocyclic alkyl or —CORi 2 (wherein Ri 2 is as defined above)
- a compound (lb) and R 3 and R 4 are the same or different and are substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl, substituted or unsubstituted aralkyl
- a compound (Ic) which is a substituted or unsubstituted aromatic heterocyclic alkyl or —CORi 2 (wherein Ri 2 has the same meaning as described above) is disclosed in,
- Step 1 Compound (II) which is commercially available or obtained by, for example, the method described in WO03 / 35639 or JP-A-11-193281 or a method analogous thereto, 1 to 200 equivalents, preferably 1 to 5 equivalents of a halogenating agent, in a solvent-free or inert solvent, and at a temperature between 30 ° C and
- the solvent inert to the reaction is not particularly limited. For example, acetone, 1,4-dioxane, acetonitrinol, chlorohonolem, dichloromethane, tetrahydrofuran
- Process 2 Compound (la) comprises compound (III) with 1 to 20 equivalents of thiourea in a solvent inert to the reaction, at a temperature between ⁇ 30 ° C. and 150 ° C., preferably between room temperature and 100 ° C. By reacting at a temperature between 5 minutes and 48 hours.
- the solvent inert to the reaction is not particularly limited, and examples thereof include toluene, hexane, THF, DMF, ethanol, and acetonitrile, and these can be used alone or in combination.
- Step 3 Compound (lb) is obtained by mixing the compound (III) without solvent or in a solvent inert to the reaction, optionally in the presence of 1 to 100 equivalents of base:! To 100 equivalents of I ⁇ .
- X 1 (wherein R 4a has the same meaning as above, and X 1 has the same meaning as the above X) and a reaction at a temperature between 30 ° C. and 150 ° C. for 5 minutes to 48 hours. Can be manufactured.
- the solvent inert to the reaction is not particularly limited, but for example, acetonitrile, dichloromethane, 1,2-dichloroethane, chloroquinolem, 1,2-dimethoxetane, DMF, N, N-dimethylacetamide (DMA ), 1, 4 mono-dioxane, THF, diethyl ether, disopropyl ether, benzene, toluene, xylene, pyridine,
- N, N-dimethylimidazolidinone (DMI), N-methylpyrrolidone ( ⁇ P), sulfolane and the like can be mentioned, and these can be used alone or in combination.
- the base include pyridine, triethylamine, diisopropylethylamine, N-methinoremo ⁇ "holin, N-methy ⁇ / piperidine, 1,8-diazabicyclo [5.4,0] (DBU), N, N-dimethylaminopyridine (DMAP), potassium acetate, potassium carbonate, cesium carbonate, sodium carbonate, sodium bicarbonate, sodium hydroxide, lithium zk acid, lithium hydroxide, phosphoric acid These may be used alone or in combination of two or more of them, etc.
- Step 4 Compound (Ic) is obtained by using compound (lb) in a solvent-free or inert solvent. 1 to 100 equivalents of R 3 aX 2 (wherein R 3 a has the same meaning as above, and X 2 has the same meaning as X) in the presence of 1 to 100 equivalents of a base, if necessary. Reaction for 5 minutes to 48 hours at temperatures between ° C and 150 ° C The inert solvent is possible.
- Reaction be prepared by, but not limited, for example Asetonitoriru, dichloroethylene Rorometan, 1, 2-dichloroethylene every mouth ethane, Kurorohonoremu, 1, 2-dimethyl Tokishetan, Examples include DMF, DMA, 1,4-dioxane, THF, jetyl ether, diisopropyl ether, benzene, toluene, xylene, pyridine, DMI, NMP, and sulfolane. These can be used alone or in combination. be able to.
- Examples of bases include pyridine, triethylamine, disopropylethylamine, N-methylmorpholine, N-methylbiperidine, DBU, DMAP, potassium acetate, carbonated lithium, cesium carbonate, sodium carbonate, sodium hydrogen carbonate, sodium hydroxide. , Lithium hydroxide, potassium hydroxide, potassium phosphate, etc., which can be used alone or in combination of two or more.
- the compound (Ib-i) in which R 3 is a hydrogen atom and R4 is COR has the following steps: Can also be manufactured.
- Step 5 Compound (Ib-i) is compound (la) in a solvent that is inert to the reaction without solvent or in a 1 to raw solvent. 1 to 100 equivalents of (R 2 CO) 2 O (wherein R12 is as defined above) or Ri 2 COCl (wherein Ri 2 is As described above) and a reaction at a temperature between 30 ° C. and 150 ° C. for 5 minutes to 48 hours.
- the solvent inert to the reaction is not particularly limited.
- Examples of the base include pyridine, triethylamine, disopropylethylamine, N-methylmorpholine, N-methylbiperidine, D'BU, DMAP, potassium acetate, carbonic acid lithium, cesium carbonate, sodium carbonate, sodium hydrogen carbonate, Sodium hydroxide , Lithium hydroxide, potassium hydroxide, potassium phosphate, etc., which can be used alone or in combination of two or more.
- compound (Ib-i) may be prepared by adding compound (la) in an appropriately inert solvent in the presence of 1 to 30 equivalents of a condensing agent, and optionally adding 1 to 30 equivalents.
- R 12 COOH (wherein R 12 is as defined above) are reacted at a temperature between 30 ° C. and 100 ° C. for 5 minutes to 48 hours. Can also be manufactured.
- the solvent inert to the reaction is not particularly limited. For example, acetonitrile, dichloromethane, 1,2-dichloroethane, chloroform, 1,2-dimethoxyethane, DMF, DMA, 1,4-dioxane, THF, Examples include jetyl ether, diisopropyl ether, benzene, toluene, xylene, pyridine, DML NMP, sulfolane, and water. These can be used alone or in combination.
- condensing agent examples include dicyclohexyl carpositimide (DCC), diisopropyl carpositimide, N— (3-dimethylaminopropyl) 1 N, monoethyl carpositimide (EDC), EDC hydrochloride, benzotriazole _ 1 _i Examples include ru-tris (dimethylamino) phosphonium hexafluorophosphate (BOP), benzotriazole-1-yl-tripyrrolidinophosphonium hexafluorophosphate (PyBOP), and diphenylphosphoryl azide (DPPA). .
- DCC dicyclohexyl carpositimide
- EDC monoethyl carpositimide
- EDC hydrochloride EDC hydrochloride
- benzotriazole _ 1 _i Examples include ru-tris (dimethylamino) phosphonium hexafluorophosphate (BOP), benzotri
- R 3 is a hydrogen atom
- R 4 force S—COR i 2h [wherein R 12h has the nitrogen atom in the definition of R 12 and has the nitrogen atom
- R1 3 and are as defined above or one ORIS (wherein Ri 5 represents the same as above.]
- (Ib-ii) can also be produced according to the following steps.
- the solvent inert to the reaction is not particularly limited.
- DMF or DMA is preferred.
- Examples of phosgene equivalents include triphosgene, 1,1, and carbo- imidazole (CDI).
- Step 7 Compound (Ib-ii) is prepared from compound (IV) in the absence of solvent or in a solvent inert to the reaction, as required 1 to: 1 to 200 equivalents of HR h in the presence of L00 equivalents of base. (Wherein is as defined above) and can be produced by reacting at a temperature between 30 ° C. and 150 ° C. for 5 minutes to 72 hours.
- the solvent inert to the reaction is not particularly limited.
- acetonitrile, dichloromethane, chloroform / rem, 1,2-dichloroethane, 1,2-dimethoxetane, DMF ⁇ DMA ⁇ 1,4 monodioxane, THF examples include tilether, diisopropyl ether, benzene, toluene, xylene, DMI, NMP, sulfolane, water, and the like. These can be used alone or in combination. Of these, DMF or DMA is preferred.
- the base include triethylamine, disopropylethylamine, DBU and the like.
- n is 0, and R 2 a [wherein R is a substituent having a nitrogen atom in the definition of R 2 and bonded to the thiazole ring at the nitrogen atom.
- R 2 a which is an unsubstituted alicyclic heterocyclic group or one NR 5 R 6 (wherein R 5 and each are as defined above), can be produced according to the following steps. it can.
- Step 8 - Compound (Ia-i) are commercially available, or for example Jananore-O Bed 'candy Jamaican Chemical' Society (J. Am. Chem. Soc .;), Vol. 72, p.3722 (1953), etc., or a compound (V) obtained by a method analogous thereto, for example, Journal of Chemical ⁇ It can be produced by the method described in Society (J. Chem. So), p. 114 (1947), or a method based on them.
- compound (Ia-i) is obtained by reacting compound (V) in a solvent inert to the reaction at a temperature between 1 to 20 equivalents of an odorizing agent and 1300 ° C to the boiling point of the solvent used. It can be produced by reacting for 5 minutes to 48 hours.
- the solvent inert to the reaction is not particularly limited, and examples thereof include dichloromethane, chloroform, 1,2-dichloroethane, and these can be used alone or in combination.
- Brominating agents include N-prosuccinimide, bromine, N, N, N, N-tetra and n-butyl ammonium bromide.
- Step 9 Among compounds (Id), compound (Id-i) in which R 3 and R 4 are hydrogen atoms is produced by using compound (Ia-i), for example, by the method described in EP518731 or a method analogous thereto. can do. That is, the compound (Id-i) is obtained by converting the compound (Ia-i) from 1 to 200 equivalents of HR in the presence of 100 equivalents of a base in the absence of a solvent or in a solvent inert to the reaction. 2 a (wherein R 2 a has the same meaning as above) and a temperature of _30 ° C. to 150 ° C. for 5 minutes to 72 hours. Inactive to the reaction 1 "raw solvent is not particularly limited.
- examples include toxetane, DMF, DMA, 1,4-dioxane, THF, jetyl ether, diisopropyl ether, benzene, toluene, xylene, DMI, NMP, sulfolane, and water. These can be used alone or in combination.
- DMF or DMA is preferable
- Bases include, for example, triethylamine, diisopropylethylamine, DBU, potassium carbonate, sodium hydroxide, etc.
- Step 1 0 of compounds (Id), R 3 is hydrogen. an atom, R 4 is R 4 a (said R 4 a are as defined above), compound (Id-ii) is used a compound (Wi), the production method 1 Degree 3 and can be granulated by the same method.
- Step 1 1 Compound (Id), R 3 and R 4 are each R 3 a (the R 3 a is as defined above) and (the Is the same as defined above) Compound (Id-iii) can be produced using Compound (Id-ii) by the same method as in Step 4 of Production Method 1.
- P represents a protecting group
- the protecting group includes, for example, tert-butoxycarbol. (Boc group), benzenoreoxycarbonyl (Z group), benzyl, acetyl, benzoyl, etc.)
- Step 1 2 Using the compound (Ia-i) obtained in Step 8 of Production Method 4, for example, protective group Listed by Protective Groups in Organic Syntnesis, TW Greene, John Wiley & Sons Inc. (1981), etc.
- the compound (VI) can be produced according to the method for introducing a protecting group into the amino group.
- the compound (Vl-i) in which P is a Boc group is obtained by replacing the compound (Ia-i) with 1-30 equivalents of a base in a solvent inert to the reaction as necessary. In the presence, it can be produced by reacting for 1 to 30 equivalents of dicarbonate-tei't-butyl and at a temperature between 30 ° C. and the boiling point of the solvent used for 5 minutes to 48 hours. . .
- the solvent inert to the reaction is not particularly limited.
- Step 1 3 Compound (VII) is obtained by reacting Compound (VI) with 1 to 100 equivalents of a formylating agent in the presence of 1 to 20 equivalents of a base in a solvent inert to the reaction, at a temperature of 78 ° C to room temperature.
- the solvent inert to the reaction is not particularly limited, and examples thereof include THF, jetyl ether, 1,4-dioxane, 1,2-dimethoxetane, hexane, and the like. These may be used alone or in combination. Can do.
- formylating agents include DMF, N-methyl_N-phenylformamide, N-methyl-1-N- (2-pyridyl) formamide, morpholinoformamide, and the like. Of these, DMF is preferred.
- Examples of the base include lithium diisopropylamide, lithium bis (trimethylsilyl) amide, methyllithium, n-butyllithium, lithium hydride, sodium hydride 1, lithium, potassium hydride, methylmagnesium bromide, and acetylbromide bromide.
- Examples thereof include magnesium and isopropyl chloride, and these can be used alone or in combination of two or more.
- Step 1 4 Using Compound (VII), for example, Protective Groups m Organic Synthesis, Green (TW Greene, John Wiley and Sands Incorporated (John Wiley & Sons Inc.) (1981) etc.
- pre-beta 4 can be prepared a compound having a hydrogen atom (Ie-i), if P is Boc group, the compound (Ie-i), the compound (VII), or the reaction solvent-free In an inert solvent, it can be produced by treating with an equivalent amount of acid to a large excess of acid at a temperature of _3 (? ° C to 150 ° C for 5 minutes to 48 hours.
- the active solvent include, but are not limited to, dichloromethane, chloroform, 1,2-dichloroethane, methanol, ethanol, THF, ethyl acetate, water, and the like. These may be used alone or in combination.
- Step 1 5 Among the compounds (Ie), R 3 is a hydrogen atom, R 4 is R 4 a (the R 4 a is as defined above)
- the compound (le-ii) is synonymous with the compound (Ie-i) It can be produced by the same method as in Step 3 of Production Method 1.
- Step 1 6 Among compounds (Ie), R 3 is R 3 a (wherein R 3 a is as defined above), and R 4 is R 4 a (the
- Compound (Ie-iii) is the compound (le-ii) used can be prepared in the same manner as 4 as of Preparation 1 E.
- Step 17 Compound (1) is obtained by reacting Compound (Ie-i), Compound (le-ii) or Compound (Ie-iii) in the presence of 1 to 50 equivalents of a reducing agent in a solvent inert to the reaction. 1 to 200 equivalents of HNR 6 (wherein R 5 and R 6 are as defined above) and a temperature between 30 ° C. and the boiling point of the solvent used for 5 minutes to 48 hours. Can be manufactured.
- Examples of the reducing agent include sodium triacetoxyborohydride, sodium borohydride, sodium cyanoborohydride, and the like. Of these, triacetoxy sodium borohydride is preferable.
- the solvent inert to the reaction is not particularly limited, but for example, methanol, ethanol, dichloromethane, chlorophenol, 1,2-dichloroethane, THF, 1,4-dioxane, jetinoreethenole, diisopropinore Examples include etherol, benzene, toluene, xylene, DMF, and water, which can be used alone or in combination.
- R2 is -COOH (Ih) and R2 is -cORSb [wherein
- R 8b is a substituted or unsubstituted alicyclic heterocyclic group having a nitrogen atom and bonded to —CO— of one COR 8 in the above definition of R 8 or one NR 9 Rio (wherein , R 9 and Rio are the same as defined above], respectively, can also be produced according to the following steps.
- Ri, RK R4, R8b and n are as defined above, and Riia represents lower alkyl or benzyl in the definition of Rii
- R 2 force S—COORUa where R lla is as defined above
- Ig Protective Groups in “Ocanic” Synthesis (Protective Groups in According to the method for removing protecting groups described in Organic Synthesis ;, by TW Greene, John Wiley & Sons Inc.
- compound (Ih) when R lla is methyl or ethyl, compound (Ih) can be prepared by combining compound (Ig) with 1 equivalent to a large excess of base in a solvent containing water. At a temperature between ° C and the boiling point of the solvent used, for 5 minutes
- the solvent is not particularly limited, but for example, methanol, ethanol, propanol, THF, 1,4-dioxane, 1,2-dimethoxetane, toluene, dichloromethane, DMF and the like, as these may be used alone or as a mixture.
- base such hydroxide Natoriumu, hydroxide force Riumu, such as lithium hydroxide.
- Riia is t er t-
- compound (Ih) is obtained by converting compound (Ig) from 1 equivalent to a large excess of acid in a solvent-free or solvent inert to the reaction, from 30 ° C to: 100 ° It can be produced by treating at a temperature between C for 5 minutes to 48 hours.
- the solvent inert to the reaction is not particularly limited.
- Step 1 9 Compound (Ii) is prepared from 1 to 30 equivalents of compound (111) in the presence of 1 to 30 equivalents of a suitable condensing agent in an insoluble solvent or in an inert solvent. 1 to 100 equivalents of HR 8 b (wherein R 8 b is as defined above) and a temperature between 30 ° C. and 100 ° C. for 5 minutes. It can be produced by reacting for 72 hours.
- the solvent inert to the reaction is not particularly limited.
- acetonitrile dichloromethane, 1,2-dichloroethane, chlorophenol, 1,2-dimethoxetane, DMF, DMA, 1,4-dioxane, THF, jetyl ether , Diisopropyl ether, benzene, toluene, xylene, pyridine, DMI, NMP, sulfolane, water and the like.
- the condensing agent include DCC, disopropyl carbodiimide, EDC, EDC hydrochloride, BOP, PyBOP, DPPA and the like.
- R 2 is one Corse (wherein, represents a substituted or unsubstituted lower alkyl of definition of R 8, substituted or unsubstituted lower alkenyl, substituted or unsubstituted Lower alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted alicyclic heterocyclic group, substituted or unsubstituted alicyclic heterocyclic alkyl,
- the compound (') which represents a substituted or unsubstituted aromatic heterocyclic group or a substituted or unsubstituted aromatic heterocyclic alkyl can also be produced according to the following steps.
- Step 20 Compound (Ij) 1 to 50 equivalents of R8cM in the solvent inert to the reaction (wherein R8 C is as defined above, M is MgCl, MgBr, Mgl, Li , ZnCH 3 , ZnC CH 3 , Ti (OCH (CH 3 ) 2) 3 and the like) and reaction at a temperature between 78 ° C and the boiling point of the solvent used for 5 minutes to 48 hours. Can be manufactured.
- the solvent inert to the reaction is not particularly limited, and examples thereof include jetyl ether, THF, 1,4-dioxane, 1,2-dimethoxetane, toluene, and the like. These may be used alone or in combination.
- Ra is a lower alkoxy as defined above or one NRblRb 2 (wherein Rbl and Rbl are the same or different and each represents a lower alkyl as defined above or a lower alkoxy as defined above.
- Step 2 1 Compound (Ij-i) is obtained by reacting Compound (Ik) in a solvent inert to the reaction in the presence of 1 to 20 equivalents of base 1 to: 100 equivalents of Rsc—CORa And a reaction at a temperature between 78 ° C. and room temperature for 5 minutes to 48 hours.
- the compound (Ik) used as a raw material is the compound (Ia_i) obtained in Step 8 of Production Method 4, or Step 3 of Production Method 1 or Step 3 and Step 4 of Production Method 1 from the compound (Ia-i).
- a compound obtained by the same method can be used.
- the solvent inert to the reaction include, but are not limited to, THF, jetyl ether, 1,4-dioxane, 1,2-dimethoxetane, hexane, and the like. These may be used alone or in combination. Can do.
- Step 2 2 Compound (Ii) is obtained by converting Compound (Ik) from 1 to 100 equivalents of RSaCHO in the presence of 1 to 20 equivalents of base in a solvent inert to the reaction, and between 78 ° C and room temperature. At a temperature of 5 minutes to 48 hours.
- Examples of the solvent inert to the reaction include, but are not limited to, THF, jetyl ether, 1,4-dioxane, 1,2-dimethoxetane, hexane, and the like. These may be used alone or in combination.
- Examples of bases include lithium disopropylamide, lithium bis ( ⁇ limethylol silyl) amide, methyl lithium, n-butyl lithium, lithium hydride, sodium hydride, hydrogen hydride, methyl magnesium bromide, bromide
- Examples thereof include tilmagnesium and isopropyl chloride chloride, and these can be used alone or in combination of two or more. 'Etc. can be mixed and used.
- Step 2 3 Compound (Im) is obtained by reacting Compound (Ie) obtained in Production Method 5 with 1 to 50 equivalents of RScM in the reaction inert solvent (wherein, 8 and M are as defined above). And at a temperature between 78 ° C. and the boiling point of the solvent used for 5 minutes to 48 hours.
- the solvent inert to the reaction is not particularly limited, and examples thereof include jetyl ether, THF, 1,4-dioxane, 1,2-dimethoxyethane, toluene and the like. These may be used alone or in combination. be able to.
- Step 2 4 Compound is compound (Im) in the absence of solvent or in a reaction inert solvent with 1 to: L00 equivalent of oxidizing agent at a temperature between 78 ° C. and the boiling point of the solvent for 5 minutes. Can be produced by processing for ⁇ 48 hours.
- the solvent inert to the reaction is not particularly limited.
- acetonitrile for example, acetonitrile, dichloromethane, 1,2-diethyl ethane, chlorophenol, 1,2-dimethoxyethane, DMF, DMA, 1,4-dioxane,
- Examples include THF, jetyl ether, diisopropyl ether, benzene, toluene, xylene, pyridine, DMI, NMP, sulfolane, and water, and these can be used alone or in combination.
- acidifying agents include chromic acid, potassium, pyridinium rochromate ('PCC), pyridinium dichromate (PDC), dimethyl sulfoxide (DMSO) -oxalyl chloride, DMSO-dioxyhexylimide (DCC), Propyl ammonium perruthemate (TPAP), Dess-Martin reagent (DMP: 1, 1 1 Triacetoxy 1, 1-dihydro _ 1, 2 Benzododoxol 3 (1 H) One , Experimental Chemistry Course 5th edition, 15th page, p.27, edited by The Chemical Society of Japan, Maruzen (2003)), 2--Odoxylbenzoic acid (IBX), 2, 2, 6, 6-tetramethylpiperidine Examples include N-oxide (TEMPO) and manganese dioxide.
- TEMPO N-oxide
- manganese dioxide manganese dioxide
- conversion of the functional group contained in RRR 3 or R 4 in compound (I) can be performed by other known methods [eg, Comprehensive Organic Transformations, RC It can also be carried out by the method described in the article by Larock (1989) or the like.
- the compound (I) having a desired functional group at a desired position can be obtained by carrying out a combination of the above methods as appropriate. Separation and purification methods commonly used in, for example, filtration, extraction, washing, drying, concentration, recrystallization, and various chromatographies can be used for isolation and purification. Further, the intermediate can be subjected to the next reaction without any particular purification.
- Some compounds (I) may have isomeric isomers, such as positional isomers, geometric isomers, optical isomers, tautomers, etc. Forces that can be used for the adenosine A 2A receptor antagonists of the present invention or the like, or are included in the present invention.
- a salt of Compound (I) it can be purified as it is when Compound (I) is obtained in the form of a salt, and when it is obtained in a free form, Compound (I) can be obtained in an appropriate solvent. It may be isolated or purified by dissolving or suspending in water and forming a salt by adding acid or base.
- Compound (I) and pharmacologically acceptable salts thereof may exist in the form of adducts with water or various solvents. These adducts are also present in the adenosine A 2A receptor of the present invention. Forces that can be used for body antagonists and the like are encompassed by the present invention. Specific examples of compound (I) obtained by this effort are shown in Tables 1-8. However, the compound used in the present invention or the compound of the present invention is not limited thereto. Table 1
- Test Example 1 Adenosine Receptor Binding Action (Adenosine A 2A Receptor Binding Test) The test was performed according to Bruns et al.'S method L Molecular Pharmacology, No. 29, .331 (1986)]. Rat (SD rat, Japan SLC) Polytron homogenizer (Kinematica) in 50 mL of 50 mmol / L tris (hydroxymethyl) aminomethane 'hydrochloride (TrisHCl) buffer (pH 7.7) cooled with ice Made).
- TrisHCl tris (hydroxymethyl) aminomethane 'hydrochloride
- the mixture was allowed to stand at 25 ° C for 120 minutes, then rapidly suction filtered on a glass fiber filter (GF / C; manufactured by Whatman), and immediately washed three times with 200 pL of 50 mmol / L TrisHCl buffer that had been frozen. .
- the glass fiber filter paper was transferred to a vial bottle, a mouth cinch (manufactured by Perkin Elma) was added, and the amount of radioactivity was measured with a top count (manufactured by Perkin Elmer).
- the inhibition rate of the test compound against adenosine A 2A receptor binding ( 3 H-CGS21680 binding) was calculated by the following formula. Amount of binding in the presence of drug—non-specific binding amount
- the total binding amount is the amount of 3 H-CGS21680 binding radioactivity in the absence of the test compound.
- the non-specific binding amount is the amount of radioactivity bound to 3 H-CGS21680 in the presence of ⁇ / L cyclopentyl adenosine (CPA; manufactured by Sigma).
- CCA cyclopentyl adenosine
- the amount of binding in the presence of the drug ' is 3H-CGS 21680 binding radioactivity in the presence of test compound 10- 7 mol / L.
- Compound (I) has a strong antagonism against adenosine A 2A receptor
- drugs containing Compound (I) as an active ingredient are various types involving adenosine A 2A receptor.
- Diseases eg Parkinson's disease, Alzheimer's disease, progressive supranuclear palsy, AIDS encephalopathy, disseminated spongiform encephalopathy, multiple sclerosis, amyotrophic lateral sclerosis, Huntington's disease, multiple system atrophy, brain Ischemia, attention deficit hyperactivity! ⁇ Harm, sleep disorder, intermittent claudication, diabetes, anxiety disorder (panic attacks and panic disorder, phobia, threatening disorder, post-traumatic stress disorder, acute stress disorder Generalized anxiety disorder, physical disability or substance anxiety), mood disorder
- Parkinson's disease is a disease based on degeneration / dropout of nigrostriatal dopamine nerve.
- the dopamine neurotoxin causes selective substantia nigra striatal dopamine nerve degeneration / dropout, leading to symptoms such as ataxia / muscular rigidity.
- This primate treated with M.PTP is known as a model of Parkinson's disease [Proceedings of the National Academy of Science USA), No. 80, p.4546
- the common marmoset belongs to the monkeys and is known to exhibit Parkinson's disease symptoms by MPTP like other monkeys [Neuroscience Letters
- the dyskinetic score before administration of the test compound was scored, and the test compound (Compound 1) was compared with the dyskinetic score after oral administration of lOmg / kg.
- Parkinson's disease symptoms were observed through a one-way fluoroscopy window every 30 minutes for 8 hours and scored for dyskinetics. Spontaneous momentum was measured every 30 minutes up to 12 hours using a computer-controlled automatic measuring device. Parkinson's disease symptoms were determined based on the following criteria and totaled for the following observation items: The score was taken as the individual's score. Table 10 below shows the relationship between observation items and scores. Table 10 'Observed item Score 0 1 2 3 4 Reminder Normal Decrease Sleep tendency Uplifting Decrease None Blink behavior Normal Abnormal Trunk, tail, limb
- the result was determined by comparing the average scores of Parkinson's disease symptoms of 4 animals per group before and after administration of Compound 1 [significant difference test: Wilcoxon Rank Sum test]. As a result, Compound 1 was shown to relieve Parkinson's disease symptoms in the above test, and Compound (I) was suggested to be effective for the treatment and / or prevention of Parkinson's disease.
- Compound (I) or a pharmacologically acceptable salt thereof can be administered alone as it is, but it is usually desirable to provide it as various pharmaceutical preparations. These pharmaceutical preparations are used for animals or humans.
- the pharmaceutical preparation according to the present invention may contain Compound (I) or a pharmacologically acceptable salt thereof as an active ingredient alone or as a mixture with any other active ingredient for treatment.
- these pharmaceutical preparations are pharmacologically acceptable for the active ingredient 1 It is mixed with seeds or more carriers and prepared by any method well known in the pharmaceutical arts.
- oral or parenteral such as intravenous administration can be mentioned.
- the dosage form include tablets and injections. Suitable for oral administration, such as tablets, excipients such as lactose, mannitol, disintegrants such as starch, lubricants such as magnesium stearate, binders such as hydroxypropylcellulose, fatty acid esters, etc. It can be produced using a surfactant, a plasticizer such as glycerin.
- Formulations suitable for parenteral administration preferably comprise a sterile aqueous solution containing the active compound that is isotonic with the blood of the recipient.
- a solution for injection is prepared using a carrier made of a salt solution, a pudou sugar solution, or a mixture of salt water and a glucose solution.
- One or more trapping ingredients can also be added.
- Compound (I) or a pharmacologically acceptable salt thereof is usually administered systemically or locally in an oral or parenteral form when used for the above purpose.
- the dose is preferably in the range of 0.05 to 500 mg once to several times a day.
- parenteral administration such as intravenous administration, usually 0.001 to 1000 mg, preferably 0.01 to 300 mg per adult is administered once to several times a day, or intravenously in the range of 1 to 24 hours per day. Administer continuously.
- the title compound 8 (126 mg, 30%) was obtained from the compound a (300 mg, 1.23 mmol) obtained in Reference Example 1 using 2.46 mmol). .
- Methyl 6-chloromethylnicotinate (1.30 g, 7.00 mmol) obtained by the method described in WO02 / 92455 was added to 2 mol / L hydrochloric acid, and the mixture was stirred for 5 hours with heating under reflux. The reaction solution is allowed to cool to room temperature, and the precipitated solid is collected by filtration to give 6-chloromethylnicotinic acid.
- Step 1 1- (N., N-dimethylcarpamoyl) piperidine monoethyl carbonate (2.28 g, 10.0 mmol) obtained in Step 1 was mixed with methanol (30 mL) and water (10 mL). Into the solution, lithium hydroxide monohydrate (2'.10 g, 50.0 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure, and 6 mol / L hydrochloric acid was added to the resulting residue to adjust the pH to 1, followed by extraction with black mouth form.
- Step 3 'Dissolve 1- (N, N_dimethylcarbamoyl) piperidine mono 4-canolepo' acid (300 mg, 1.50 mmol) obtained in Step 2 in dichloromethane (15 mL) and thionyl chloride (0.547 mL) , 7.50 mmol) was added, and the mixture was stirred for 1 hour with heating under reflux.
- the reaction solution was concentrated under reduced pressure, and the resulting residue was dissolved in black mouth form (5 mL).
- the resulting solution was added to a pyridine (10 mL) solution of 2-amino-4 one (.2-furyl) -5 one morpholinothiazole (126 mg, 0.50 mmol) obtained in step 1 of Example 29. Stir at room temperature for 1 hour.
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Priority Applications (19)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2005516733A JP4638355B2 (ja) | 2003-12-26 | 2004-12-24 | チアゾール誘導体 |
BRPI0418082A BRPI0418082B8 (pt) | 2003-12-26 | 2004-12-24 | derivados de tiazol úteis como antagonistas de receptor de adenosina a2a |
KR1020067012796A KR101168625B1 (ko) | 2003-12-26 | 2004-12-24 | 티아졸 유도체 |
PL04808128T PL1700856T3 (pl) | 2003-12-26 | 2004-12-24 | Pochodna tiazolu |
EP04808128.5A EP1700856B1 (en) | 2003-12-26 | 2004-12-24 | Thiazole derivative |
US10/584,633 US7718808B2 (en) | 2003-12-26 | 2004-12-24 | Thiazole derivatives |
EA200601235A EA013249B1 (ru) | 2003-12-26 | 2004-12-24 | Производные тиазола |
SI200432290T SI1700856T1 (sl) | 2003-12-26 | 2004-12-24 | Tiazolni derivat |
CA2551611A CA2551611C (en) | 2003-12-26 | 2004-12-24 | Thiazole derivatives for treating or preventing parkinson's disease |
CN2004800389300A CN1902196B (zh) | 2003-12-26 | 2004-12-24 | 噻唑衍生物 |
DK04808128.5T DK1700856T3 (en) | 2003-12-26 | 2004-12-24 | thiazole |
AU2004309279A AU2004309279B2 (en) | 2003-12-26 | 2004-12-24 | Thiazole derivative |
ES04808128.5T ES2555308T3 (es) | 2003-12-26 | 2004-12-24 | Derivado de tiazol |
ZA2006/06027A ZA200606027B (en) | 2003-12-26 | 2006-07-20 | Thiazole derivative |
NO20063446A NO338017B1 (no) | 2003-12-26 | 2006-07-26 | Tiazolderivater, farmasøytiske preparater inneholdende slike, og anvendelse derav |
HK06113527.9A HK1091837A1 (en) | 2003-12-26 | 2006-12-08 | Thiazole derivative |
US12/766,986 US7880013B2 (en) | 2003-12-26 | 2010-04-26 | Thiazole derivatives |
US12/960,937 US8420827B2 (en) | 2003-12-26 | 2010-12-06 | Thiazole derivatives |
US13/826,654 US8889718B2 (en) | 2003-12-26 | 2013-03-14 | Thiazole derivatives |
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JP2003-432777 | 2003-12-26 | ||
JP2003432777 | 2003-12-26 |
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US10/584,633 A-371-Of-International US7718808B2 (en) | 2003-12-26 | 2004-12-24 | Thiazole derivatives |
US12/766,986 Division US7880013B2 (en) | 2003-12-26 | 2010-04-26 | Thiazole derivatives |
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PCT/JP2004/019778 WO2005063743A1 (ja) | 2003-12-26 | 2004-12-24 | チアゾール誘導体 |
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US (4) | US7718808B2 (ja) |
EP (2) | EP3002283B1 (ja) |
JP (1) | JP4638355B2 (ja) |
KR (1) | KR101168625B1 (ja) |
CN (1) | CN1902196B (ja) |
AU (1) | AU2004309279B2 (ja) |
BR (1) | BRPI0418082B8 (ja) |
CA (1) | CA2551611C (ja) |
CY (2) | CY1117132T1 (ja) |
DK (2) | DK3002283T3 (ja) |
EA (1) | EA013249B1 (ja) |
ES (2) | ES2555308T3 (ja) |
HK (1) | HK1091837A1 (ja) |
HU (1) | HUE025659T2 (ja) |
LT (1) | LT3002283T (ja) |
NO (1) | NO338017B1 (ja) |
PL (2) | PL3002283T3 (ja) |
PT (2) | PT1700856E (ja) |
SI (2) | SI1700856T1 (ja) |
TW (1) | TWI349550B (ja) |
WO (1) | WO2005063743A1 (ja) |
ZA (1) | ZA200606027B (ja) |
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